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1
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Gong H, Nie D, Li Z. The crosstalk between broad epigenetic modification and T cell metabolism within tumor microenvironment. Int Immunopharmacol 2025; 152:114410. [PMID: 40068521 DOI: 10.1016/j.intimp.2025.114410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 03/01/2025] [Accepted: 03/02/2025] [Indexed: 03/24/2025]
Abstract
T cells play an important role in adaptive immune responses, providing antigen specificity for pathogen and tumor recognition. Recent studies have elucidated the complex interplay between T cell metabolism and broad epigenetic modifications in response to tumors, occurring at transcriptional, post-transcriptional, and post-translational levels. At the transcriptional level, gene expression is regulated through mechanisms such as DNA methylation, chromatin remodeling, and transcription factor activity. Post-transcriptionally, gene expression is further modulated by non-coding RNAs and RNA modifications, an area of increasing research interest. In addition, histone proteins are primarily regulated by well-established post-translational modifications (PTMs), including acetylation and methylation. Novel PTMs such as succinylation, glycosylation, glutamylation, and lactylation add complexity to the regulation and warrant further investigation. At present, the interaction between CD8+ T cell metabolism and epigenetic modifications in response to malignancies has been reported extensively. However, the interplay in CD4+ T cells remains less understood. In this review, we introduce the differentiation trajectories of T cells and critically evaluate existing interplay between metabolic activity and epigenetic modifications influences the functional dynamics in both CD8+ and CD4+ T cells, offering promising avenues for the development of novel cancer immunotherapies.
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Affiliation(s)
- Han Gong
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Dan Nie
- Department of Obstetrics and Gynecology, The affiliated hospital of Southwest Medical University, Luzhou 646000, People's Republic of China
| | - Zhengyu Li
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
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2
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Yee Mon KJ, Kim S, Dai Z, West JD, Zhu H, Jain R, Grimson A, Rudd BD, Singh A. Functionalized nanowires for miRNA-mediated therapeutic programming of naïve T cells. NATURE NANOTECHNOLOGY 2024; 19:1190-1202. [PMID: 38684809 PMCID: PMC11330359 DOI: 10.1038/s41565-024-01649-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/13/2024] [Indexed: 05/02/2024]
Abstract
Cellular programming of naïve T cells can improve the efficacy of adoptive T-cell therapy. However, the current ex vivo engineering of T cells requires the pre-activation of T cells, which causes them to lose their naïve state. In this study, cationic-polymer-functionalized nanowires were used to pre-program the fate of primary naïve CD8+ T cells to achieve a therapeutic response in vivo. This was done by delivering single or multiple microRNAs to primary naïve mouse and human CD8+ T cells without pre-activation. The use of nanowires further allowed for the delivery of large, whole lentiviral particles with potential for long-term integration. The combination of deletion and overexpression of miR-29 and miR-130 impacted the ex vivo T-cell differentiation fate from the naïve state. The programming of CD8+ T cells using nanowire-delivered co-delivery of microRNAs resulted in the modulation of T-cell fitness by altering the T-cell proliferation, phenotypic and transcriptional regulation, and secretion of effector molecules. Moreover, the in vivo adoptive transfer of murine CD8+ T cells programmed through the nanowire-mediated dual delivery of microRNAs provided enhanced immune protection against different types of intracellular pathogen (influenza and Listeria monocytogenes). In vivo analyses demonstrated that the simultaneous alteration of miR-29 and miR-130 levels in naïve CD8+ T cells reduces the persistence of canonical memory T cells whereas increases the population of short-lived effector T cells. Nanowires could potentially be used to modulate CD8+ T-cell differentiation and achieve a therapeutic response in vivo without the need for pre-activation.
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Affiliation(s)
- Kristel J Yee Mon
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA
| | - Sungwoong Kim
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, USA
| | - Zhonghao Dai
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Jessica D West
- Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, USA
| | - Hongya Zhu
- Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, USA
| | - Ritika Jain
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Andrew Grimson
- Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, USA
| | - Brian D Rudd
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
| | - Ankur Singh
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
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3
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Xu SJ, Chen JH, Chang S, Li HL. The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity. Front Immunol 2024; 14:1320305. [PMID: 38264670 PMCID: PMC10803515 DOI: 10.3389/fimmu.2023.1320305] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/20/2023] [Indexed: 01/25/2024] Open
Abstract
T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8+ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.
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Affiliation(s)
- Shi-Jun Xu
- Department of Interventional Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
- Henan Medical Device Engineering Research Center of Interventional Therapy for Non-vascular Tumors, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Jin-Hua Chen
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Suhwan Chang
- Department of Physiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Hai-Liang Li
- Department of Interventional Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
- Henan Medical Device Engineering Research Center of Interventional Therapy for Non-vascular Tumors, Henan Cancer Hospital, Zhengzhou, Henan, China
- Department of Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
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4
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Toivakka M, Gordon K, Kumar S, Bermudez-Barrientos JR, Abreu-Goodger C, Zamoyska R, Buck AH. miR-7 is recruited to the high molecular weight RNA-induced silencing complex in CD8 + T cells upon activation and suppresses IL-2 signaling. RNA (NEW YORK, N.Y.) 2023; 30:26-36. [PMID: 37879863 PMCID: PMC10726160 DOI: 10.1261/rna.079030.121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/26/2023] [Indexed: 10/27/2023]
Abstract
Increasing evidence suggests mammalian Argonaute (Ago) proteins partition into distinct complexes within cells, but there is still little biochemical or functional understanding of the miRNAs differentially associated with these complexes. In naïve T cells, Ago2 is found almost exclusively in low molecular weight (LMW) complexes which are associated with miRNAs but not their target mRNAs. Upon T-cell activation, a proportion of these Ago2 complexes move into a newly formed high molecular weight (HMW) RNA-induced silencing complex (RISC), which is characterized by the presence of the GW182 protein that mediates translational repression. Here, we demonstrate distinct partitioning of miRNAs and isomiRs in LMW versus HMW RISCs upon antigen-mediated activation of CD8+ T cells. We identify miR-7 as highly enriched in HMW RISC and demonstrate that miR-7 inhibition leads to increased production of IL-2 and up-regulation of the IL-2 receptor, the transferrin receptor, CD71 and the amino acid transporter, CD98. Our data support a model where recruitment of miR-7 to HMW RISC restrains IL-2 signaling and the metabolic processes regulated by IL-2.
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Affiliation(s)
- Matilda Toivakka
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Katrina Gordon
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Sujai Kumar
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - José Roberto Bermudez-Barrientos
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Cei Abreu-Goodger
- Institute of Ecology & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Rose Zamoyska
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Amy H Buck
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
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5
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MicroRNAs in T Cell-Immunotherapy. Int J Mol Sci 2022; 24:ijms24010250. [PMID: 36613706 PMCID: PMC9820302 DOI: 10.3390/ijms24010250] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/06/2022] [Accepted: 12/15/2022] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of restoring miRNA levels in pre-clinical models, the translation into clinics remains limited. Here, we review the current knowledge of miRNAs as T-cell targeting immunotherapeutic tools, and we offer an overview of the recent advances in miRNA delivery strategies, clinical trials and future perspectives in RNA interference technologies.
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6
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Xia S, Huang J, Yan L, Han J, Zhang W, Shao H, Shen H, Wang J, Wang J, Tao C, Wang D, Wu F. miR-150 promotes progressive T cell differentiation via inhibiting FOXP1 and RC3H1. Hum Immunol 2022; 83:778-788. [PMID: 35999072 DOI: 10.1016/j.humimm.2022.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/19/2022] [Accepted: 08/11/2022] [Indexed: 11/04/2022]
Abstract
T cells used in immune cell therapy, represented by T cell receptor therapy (TCR-T), are usually activated and proliferated in vitro and are induced to a terminally differentiated phenotype, with limited viability after transfusion back into the body. T cells exhibited a robust proliferative potential and in vivo viability in the early stages of progressive differentiation. In this study, we identified microRNAs that regulate T cell differentiation. After microRNA sequencing of the four subsets: Naïve T cells (TN), stem cell-like memory T cells (TSCM), central memory T cells (TCM）, and effector memory T cells (TEM), miR-150 was identified as the most highly expressed miRNA among the four subsets and was lowly expressed in the TSCM cells. We predicted the target genes of miR-150 miRNA and performed Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses. We observed that the target genes of miR-150 were enriched in pathways associated with T-cell differentiation. FOXP1 and RC3H1 were identified as key target genes of miR-150 in the regulation of T-cell function. We examined the effects of miR-150 on the differentiation and function of healthy donor T-cells. We observed that miR-150 overexpression promoted T-cell differentiation to effector T-cells and effector memory T-cells, enhanced apoptosis, inhibited cell proliferation and increased secretion of pro-inflammatory cytokines such as IFN-γ and TNF-α. In addition, the expressions of early differentiation-related genes (ACTN1, CERS6, BCL2, and EOMES), advanced differentiation-related genes (KLRG1), and effector-function-related genes (PRF1 and GZMB) were significantly decreased after overexpression of miR-150. Collectively, our results suggested that miR-150 can promote progressive differentiation of T cells and the downmodulation of miR-150 expression while performing adoptive immunotherapy may inhibit T-cell differentiation and increase the proliferative potential of T cells.
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Affiliation(s)
- Shengfang Xia
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jianqing Huang
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Lijun Yan
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiayi Han
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Wenfeng Zhang
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Hongwei Shao
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Han Shen
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jinquan Wang
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jinquan Wang
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Changli Tao
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dingding Wang
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Fenglin Wu
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
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7
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Rad SMAH, Halpin JC, Tawinwung S, Suppipat K, Hirankarn N, McLellan AD. MicroRNA‐mediated metabolic reprogramming of chimeric antigen receptor T cells. Immunol Cell Biol 2022; 100:424-439. [PMID: 35507473 PMCID: PMC9322280 DOI: 10.1111/imcb.12551] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 12/18/2022]
Affiliation(s)
- Seyed Mohammad Ali Hosseini Rad
- Department of Microbiology and Immunology School of Biomedical Science University of Otago Dunedin Otago New Zealand
- Center of Excellence in Immunology and Immune‐mediated Diseases Chulalongkorn University Bangkok Thailand
- Department of Microbiology Faculty of Medicine Chulalongkorn University Bangkok Thailand
| | - Joshua Colin Halpin
- Department of Microbiology and Immunology School of Biomedical Science University of Otago Dunedin Otago New Zealand
| | - Supannikar Tawinwung
- Center of Excellence in Immunology and Immune‐mediated Diseases Chulalongkorn University Bangkok Thailand
- Department of Pharmacology and Physiology Faculty of Pharmaceutical Sciences Chulalongkorn University Bangkok Thailand
| | - Koramit Suppipat
- Center of Excellence in Immunology and Immune‐mediated Diseases Chulalongkorn University Bangkok Thailand
| | - Nattiya Hirankarn
- Center of Excellence in Immunology and Immune‐mediated Diseases Chulalongkorn University Bangkok Thailand
- Department of Microbiology Faculty of Medicine Chulalongkorn University Bangkok Thailand
| | - Alexander D McLellan
- Department of Microbiology and Immunology School of Biomedical Science University of Otago Dunedin Otago New Zealand
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8
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Naqvi RA, Datta M, Khan SH, Naqvi AR. Regulatory roles of MicroRNA in shaping T cell function, differentiation and polarization. Semin Cell Dev Biol 2022; 124:34-47. [PMID: 34446356 PMCID: PMC11661912 DOI: 10.1016/j.semcdb.2021.08.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/09/2021] [Accepted: 08/07/2021] [Indexed: 12/12/2022]
Abstract
T lymphocytes are an integral component of adaptive immunity with pleotropic effector functions. Impairment of T cell activity is implicated in various immune pathologies including autoimmune diseases, AIDS, carcinogenesis, and periodontitis. Evidently, T cell differentiation and function are under robust regulation by various endogenous factors that orchestrate underlying molecular pathways. MicroRNAs (miRNA) are a class of noncoding, regulatory RNAs that post-transcriptionally control multiple mRNA targets by sequence-specific interaction. In this article, we will review the recent progress in our understanding of miRNA-gene networks that are uniquely required by specific T cell effector functions and provide miRNA-mediated mechanisms that govern the fate of T cells. A subset of miRNAs may act in a synergistic or antagonistic manner to exert functional suppression of genes and regulate pathways that control T cell activation and differentiation. Significance of T cell-specific miRNAs and their dysregulation in immune-mediated diseases is discussed. Exosome-mediated horizontal transfer of miRNAs from antigen presenting cells (APCs) to T cells and from one T cell to another T cell subset and their impact on recipient cell functions is summarized.
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Affiliation(s)
- Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago 60612, IL, USA.
| | - Manali Datta
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Samia Haseeb Khan
- Graduate School of Medicine, Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan
| | - Afsar R Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago 60612, IL, USA.
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9
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Ikumi NM, Matjila M. Preterm Birth in Women With HIV: The Role of the Placenta. Front Glob Womens Health 2022; 3:820759. [PMID: 35392117 PMCID: PMC8982913 DOI: 10.3389/fgwh.2022.820759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/08/2022] [Indexed: 01/12/2023] Open
Abstract
Maternal HIV infection is associated with an increased risk of preterm birth (PTB). However, the mechanisms underlying this increased risk in women with HIV remain poorly understood. In this regard, it is well-established that labor is an inflammatory process and premature activation of the pro-inflammatory signals (associated with labor) can result in preterm labor which can subsequently lead to PTB. HIV infection is known to cause severe immune dysregulation within its host characterized by altered immune profiles, chronic inflammation and eventually, the progressive failure of the immune system. The human placenta comprises different immune cell subsets, some of which play an important role during pregnancy including participating in the inflammatory processes that accompany labor. It is therefore plausible that HIV/antiretroviral therapy (ART)-associated immune dysregulation within the placental microenvironment may underlie the increased risk of PTB reported in women with HIV. Here, we review evidence from studies that point toward the placental origin of spontaneous PTB and discuss possible ways maternal HIV infection and/or ART could increase this risk. We focus on key cellular players in the maternal decidua including natural killer cells, CD4+ T cells including CD4+ regulatory T cells, CD8+ T cells as well as macrophages.
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10
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Perdaens O, van Pesch V. Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis. Front Neurol 2022; 12:811518. [PMID: 35281989 PMCID: PMC8913495 DOI: 10.3389/fneur.2021.811518] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/27/2021] [Indexed: 12/18/2022] Open
Abstract
Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, a low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.
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Affiliation(s)
- Océane Perdaens
- Laboratory of Neurochemistry, Institute of Neuroscience, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent van Pesch
- Laboratory of Neurochemistry, Institute of Neuroscience, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Neurology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- *Correspondence: Vincent van Pesch
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11
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Yee Mon KJ, Zhu H, Daly CWP, Vu LT, Smith NL, Patel R, Topham DJ, Scheible K, Jambo K, Le MTN, Rudd BD, Grimson A. MicroRNA-29 specifies age-related differences in the CD8+ T cell immune response. Cell Rep 2021; 37:109969. [PMID: 34758312 DOI: 10.1016/j.celrep.2021.109969] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/09/2021] [Accepted: 10/19/2021] [Indexed: 11/27/2022] Open
Abstract
MicroRNAs (miRNAs) have emerged as critical regulators of cell fate in the CD8+ T cell response to infection. Although there are several examples of miRNAs acting on effector CD8+ T cells after infection, it is unclear whether differential expression of one or more miRNAs in the naive state is consequential in altering their long-term trajectory. To answer this question, we examine the role of miR-29 in neonatal and adult CD8+ T cells, which express different amounts of miR-29 only prior to infection and adopt profoundly different fates after immune challenge. We find that manipulation of miR-29 expression in the naive state is sufficient for age-adjusting the phenotype and function of CD8+ T cells, including their regulatory landscapes and long-term differentiation trajectories after infection. Thus, miR-29 acts as a developmental switch by controlling the balance between a rapid effector response in neonates and the generation of long-lived memory in adults.
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Affiliation(s)
- Kristel J Yee Mon
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Hongya Zhu
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
| | - Ciarán W P Daly
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
| | - Luyen T Vu
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Norah L Smith
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Ravi Patel
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
| | - David J Topham
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Kristin Scheible
- Department of Pediatrics, Division of Neonatology, University of Rochester, Rochester, NY 14642, USA
| | - Kondwani Jambo
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi
| | - Minh T N Le
- Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Brian D Rudd
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
| | - Andrew Grimson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
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12
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DNA Methylation and Immune Memory Response. Cells 2021; 10:cells10112943. [PMID: 34831166 PMCID: PMC8616503 DOI: 10.3390/cells10112943] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/13/2021] [Accepted: 10/19/2021] [Indexed: 12/16/2022] Open
Abstract
The generation of memory is a cardinal feature of the adaptive immune response, involving different factors in a complex process of cellular differentiation. This process is essential for protecting the second encounter with pathogens and is the mechanism by which vaccines work. Epigenetic changes play important roles in the regulation of cell differentiation events. There are three types of epigenetic regulation: DNA methylation, histone modification, and microRNA expression. One of these epigenetic changes, DNA methylation, occurs in cytosine residues, mainly in CpG dinucleotides. This brief review aimed to analyse the literature to verify the involvement of DNA methylation during memory T and B cell development. Several studies have highlighted the importance of the DNA methyltransferases, enzymes that catalyse the methylation of DNA, during memory differentiation, maintenance, and function. The methylation profile within different subsets of naïve activated and memory cells could be an interesting tool to help monitor immune memory response.
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13
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Cannons JL, Villarino AV, Kapnick SM, Preite S, Shih HY, Gomez-Rodriguez J, Kaul Z, Shibata H, Reilley JM, Huang B, Handon R, McBain IT, Gossa S, Wu T, Su HC, McGavern DB, O'Shea JJ, McGuire PJ, Uzel G, Schwartzberg PL. PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8 + T cells at the expense of central memory. Cell Rep 2021; 37:109804. [PMID: 34644563 PMCID: PMC8582080 DOI: 10.1016/j.celrep.2021.109804] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 01/05/2023] Open
Abstract
Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cdE1020K/+ CD8+ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cdE1020K/+ CD8+ cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8+ T cell effector differentiation, providing insight into phenotypes of patients with APDS.
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Affiliation(s)
- Jennifer L Cannons
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
| | - Alejandro V Villarino
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA; Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Senta M Kapnick
- National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA
| | - Silvia Preite
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Han-Yu Shih
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA; National Eye Institute, NIH, Bethesda, MD 20892, USA
| | - Julio Gomez-Rodriguez
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; TCR2 Therapeutics, Cambridge, MA 02142, USA
| | - Zenia Kaul
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Hirofumi Shibata
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Julie M Reilley
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Bonnie Huang
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Robin Handon
- National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Ian T McBain
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Selamawit Gossa
- National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
| | - Tuoqi Wu
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; University of Colorado, Department of Immunology, Denver, CO 80204, USA; Department of Immunology and Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390
| | - Helen C Su
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Dorian B McGavern
- National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
| | - John J O'Shea
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA
| | - Peter J McGuire
- National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Gulbu Uzel
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Pamela L Schwartzberg
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
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14
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Wang Y, Qiu F, Xu Y, Hou X, Zhang Z, Huang L, Wang H, Xing H, Wu S. Stem cell-like memory T cells: The generation and application. J Leukoc Biol 2021; 110:1209-1223. [PMID: 34402104 DOI: 10.1002/jlb.5mr0321-145r] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/30/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Stem cell-like memory T cells (Tscm), are a newly defined memory T cell subset with characteristics of long life span, consistent self-renewing, rapid differentiation into effector T cells, and apoptosis resistance. These features indicate that Tscm have great therapeutic or preventive purposes, including being applied in chimeric Ag receptor-engineered T cells, TCR gene-modified T cells, and vaccines. However, the little knowledge about Tscm development restrains their applications. Strength and duration of TCR signaling, cytokines and metabolism in the T cells during activation all influence the Tscm development via regulating transcriptional factors and cell signaling pathways. Here, we summarize the molecular and cellular pathways involving Tscm differentiation, and its clinical application for cancer immunotherapy and prevention.
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Affiliation(s)
- Yutong Wang
- Department of Laboratory Medicine, Nanhai Hospital, Southern Medical University, Foshan, Guangdong, China.,Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Feng Qiu
- Department of Laboratory Medicine, Nanhai Hospital, Southern Medical University, Foshan, Guangdong, China
| | - Yifan Xu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhili Zhang
- Clinical Laboratory Department, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Lei Huang
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Huijun Wang
- Department of Laboratory Medicine, Nanhai Hospital, Southern Medical University, Foshan, Guangdong, China
| | - Hui Xing
- Department of Obstetrics and Gynecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China
| | - Sha Wu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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15
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Akbari B, Ghahri-Saremi N, Soltantoyeh T, Hadjati J, Ghassemi S, Mirzaei HR. Epigenetic strategies to boost CAR T cell therapy. Mol Ther 2021; 29:2640-2659. [PMID: 34365035 DOI: 10.1016/j.ymthe.2021.08.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/19/2021] [Accepted: 07/31/2021] [Indexed: 02/08/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has led to a paradigm shift in cancer immunotherapy, but still several obstacles limit CAR T cell efficacy in cancers. Advances in high-throughput technologies revealed new insights into the role that epigenetic reprogramming plays in T cells. Mechanistic studies as well as comprehensive epigenome maps revealed an important role for epigenetic remodeling in T cell differentiation. These modifications shape the overall immune response through alterations in T cell phenotype and function. Here, we outline how epigenetic modifications in CAR T cells can overcome barriers limiting CAR T cell effectiveness, particularly in immunosuppressive tumor microenvironments. We also offer our perspective on how selected epigenetic modifications can boost CAR T cells to ultimately improve the efficacy of CAR T cell therapy.
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Affiliation(s)
- Behnia Akbari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Navid Ghahri-Saremi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Tahereh Soltantoyeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Jamshid Hadjati
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Saba Ghassemi
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran.
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16
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Zhang Y, Wu J, Zeng C, Xu L, Wei W, Li Y. The role of NFAT2/miR-20a-5p signaling pathway in the regulation of CD8 + naïve T cells activation and differentiation. Immunobiology 2021; 226:152111. [PMID: 34237654 DOI: 10.1016/j.imbio.2021.152111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 11/25/2022]
Abstract
T cell dysfunction is a common characteristic in leukemia patients that significantly impacts clinical treatment and prognosis. However, the mechanism underlying T cell dysfunction and its reversal remains unclear. In this study, in accordance with our previous findings, we found that the expression of NFAT2 and pri-miR-17 ~ 92 are lower in peripheral blood CD3+ T cells from chronic myelogenous leukemia (CML) patients by gene expression analysis. We further demonstrate that the NFAT2-induced activation, differentiation, and expression of cytokines in human umbilical cord blood CD8+ naïve T cells are miR-20a-5p dependent. We also preliminarily explored the relationship between NFAT2 and miR-20a-5p in naive T cells. These results suggest that NFAT2 and miR-20a are crucial for regulating functional CD8+ T cells. Additionally, their alteration may be related to CD8+ T cell dysfunction in CML patients; thus, NFAT2 and miR-20a-5p may be considered potential targets for revising T cell function in leukemia immunotherapy.
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Affiliation(s)
- Yikai Zhang
- Depart of Hematology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Guangzhou Municipality Tianhe Nuoya Bio-engineering Co. Ltd, Guangzhou 510663, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China
| | - Jialu Wu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China
| | - Chengwu Zeng
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China
| | - Ling Xu
- Depart of Hematology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China.
| | - Wei Wei
- Guangzhou Municipality Tianhe Nuoya Bio-engineering Co. Ltd, Guangzhou 510663, China.
| | - Yangqiu Li
- Depart of Hematology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China.
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17
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Nazari N, Jafari F, Ghalamfarsa G, Hadinia A, Atapour A, Ahmadi M, Dolati S, Rostamzadeh D. The emerging role of microRNA in regulating the mTOR signaling pathway in immune and inflammatory responses. Immunol Cell Biol 2021; 99:814-832. [PMID: 33988889 DOI: 10.1111/imcb.12477] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 05/10/2021] [Accepted: 05/10/2021] [Indexed: 01/01/2023]
Abstract
The mechanistic/mammalian target of rapamycin (mTOR) is considered to be an atypical protein kinase that plays a critical role in integrating different cellular and environmental inputs in the form of growth factors, nutrients and energy and, subsequently, in regulating different cellular events, including cell metabolism, survival, homeostasis, growth and cellular differentiation. Immunologically, mTOR is a critical regulator of immune function through integrating numerous signals from the immune microenvironment, which coordinates the functions of immune cells and T cell fate decisions. The crucial role of mTOR in immune responses has been lately even more appreciated. MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNAs that act as molecular regulators involved in multiple processes during immune cells development, homeostasis, activation and effector polarization. Several studies have recently indicated that a range of miRNAs are involved in regulating the phosphoinositide 3-kinase/protein kinase B/mTOR (PI3K/AKT/mTOR) signaling pathway by targeting multiple components of this signaling pathway and modulating the expression and function of these targets. Current evidence has revealed the interplay between miRNAs and the mTOR pathway circuits in various immune cell types. The expression of individual miRNA can affect the function of mTOR signaling to determine the cell fate decisions in immune responses through coordinating immune signaling and cell metabolism. Dysregulation of the mTOR pathway/miRNAs crosstalk has been reported in cancers and various immune-related diseases. Thus, expression profiles of dysregulated miRNAs could influence the mTOR pathway, resulting in the promotion of aberrant immunity. This review summarizes the latest information regarding the reciprocal role of the mTOR signaling pathway and miRNAs in orchestrating immune responses.
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Affiliation(s)
- Nazanin Nazari
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Jafari
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Abolghasem Hadinia
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Amir Atapour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davood Rostamzadeh
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.,Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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18
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Kim C, Ye Z, Weyand CM, Goronzy JJ. miR-181a-regulated pathways in T-cell differentiation and aging. Immun Ageing 2021; 18:28. [PMID: 34130717 PMCID: PMC8203492 DOI: 10.1186/s12979-021-00240-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/08/2021] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are regulatory noncoding RNAs important for many aspects of cellular processes including cell differentiation and proliferation. Functions of numerous miRNAs have been identified in T cells, with miR-181a regulating T cell activation thresholds during thymic T cell development and during activation of peripheral T cells. Intriguingly, miR-181a is implicated in defective antiviral and vaccine responses in older individuals, as its expression declines in naïve T cells with increasing age. Here, we review the pathways that are regulated by miR-181a and that explain the unique role of miR-181a in T cell development, T cell activation and antiviral T cell responses. These studies provide a framework for understanding how a decline in miR-181a expression in T cells could contribute to age-related defects in adaptive immunity. We furthermore review the mechanisms that cause the age-related decline in miR-181a expression and discuss the potential of restoring miR-181a expression or targeting miR-181a-regulated pathways to improve impaired T cell responses in older individuals.
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Affiliation(s)
- Chulwoo Kim
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul, Republic of Korea.
| | - Zhongde Ye
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA.
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19
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Zhang Y, Ding N, Xie S, Ding Y, Huang M, Ding X, Jiang L. Identification of important extracellular vesicle RNA molecules related to sperm motility and prostate cancer. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2021; 2:104-126. [PMID: 39697534 PMCID: PMC11648515 DOI: 10.20517/evcna.2021.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 12/20/2024]
Abstract
Aim Many male diseases are associated with sperm quality, such as prostate cancer (PCa), oligospermia, and asthenospermia. Seminal plasma extracellular vesicles (SPEVs) play important roles in sperm function. In this study, we explored the specific RNA molecules in SPEVs that play an important role in sperm motility and found promising biomarkers of PCa in SPEVs. Methods Pigs have become an ideal model for human biomedical research. In this study, the whole transcriptome profiles of SPEVs of boars with high or low sperm motility were studied for the first time. Important long non-coding RNAs, microRNAs, and genes were identified through differentially expressed analysis and weighted correlation network analysis (WGCNA). In addition, we established a diagnosis model of PCa by differentially expressed miRNAs homologous with human. Results In total, 27 differentially expressed miRNAs, 106 differentially expressed lncRNAs, and 503 differentially expressed genes were detected between the groups. The results of WGCNA show one module was significantly associated with sperm motility (r = 0.98, FDR = 2 × 10-6). The value of highly homologous miRNAs for the diagnosis of PCa was assessed and the combination of hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-155-5p, and hsa-miR-378a-3p exhibited the highest sensitivity (AUC = 0.914). Interestingly, mRNA expression of SPEVs was mainly enriched in resting memory CD4 T cells and monocytes, and 33 cell marker genes of monocytes overlapped with the differentially expressed genes. Conclusion These data demonstrate that SPEVs of individuals with high and low sperm motility exhibit distinct transcriptional profiles, which provide valuable information for further research on diagnosis and molecular mechanism of diseases.
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Affiliation(s)
| | | | | | | | | | | | - Li Jiang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding & Reproduction, Ministry of Agriculture, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
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20
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Renrick AN, Thounaojam MC, de Aquino MTP, Chaudhuri E, Pandhare J, Dash C, Shanker A. Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1. Front Immunol 2021; 12:607044. [PMID: 33717088 PMCID: PMC7946819 DOI: 10.3389/fimmu.2021.607044] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/07/2021] [Indexed: 01/18/2023] Open
Abstract
Suppressive mechanisms operating within T cells are linked to immune dysfunction in the tumor microenvironment. We have previously reported using adoptive T cell immunotherapy models that tumor-bearing mice treated with a regimen of proteasome inhibitor, bortezomib - a dipeptidyl boronate, show increased antitumor lymphocyte effector function and survival. Here, we identify a mechanism for the improved antitumor CD8+ T cell function following bortezomib treatment. Intravenous administration of bortezomib at a low dose (1 mg/kg body weight) in wild-type or tumor-bearing mice altered the expression of a number of miRNAs in CD8+ T cells. Specifically, the effect of bortezomib was prominent on miR-155 - a key cellular miRNA involved in T cell function. Importantly, bortezomib-induced upregulation of miR-155 was associated with the downregulation of its targets, the suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1). Genetic and biochemical analysis confirmed a functional link between miR-155 and these targets. Moreover, activated CD8+ T cells treated with bortezomib exhibited a significant reduction in programmed cell death-1 (PD-1) expressing SHIP1+ phenotype. These data underscore a mechanism of action by which bortezomib induces miR-155-dependent downregulation of SOCS1 and SHIP1 negative regulatory proteins, leading to a suppressed PD-1-mediated T cell exhaustion. Collectively, data provide novel molecular insights into bortezomib-mediated lymphocyte-stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell functions. The findings support the approach that bortezomib combined with other immunotherapies would lead to improved therapeutic outcomes by overcoming T cell exhaustion in the tumor microenvironment.
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Affiliation(s)
- Ariana N Renrick
- Department of Microbiology, Immunology and Physiology, School of Medicine, Meharry Medical College, Nashville, TN, United States.,School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, United States
| | - Menaka C Thounaojam
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN, United States
| | - Maria Teresa P de Aquino
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN, United States
| | - Evan Chaudhuri
- Department of Microbiology, Immunology and Physiology, School of Medicine, Meharry Medical College, Nashville, TN, United States.,School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, United States
| | - Jui Pandhare
- Department of Microbiology, Immunology and Physiology, School of Medicine, Meharry Medical College, Nashville, TN, United States.,School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, United States.,Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN, United States
| | - Chandravanu Dash
- School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, United States.,Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN, United States.,Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN, United States.,Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University, Nashville, TN, United States
| | - Anil Shanker
- School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, United States.,Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN, United States.,Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University, Nashville, TN, United States.,Host-Tumor Interactions Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States
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21
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Wasén C, Ospelt C, Camponeschi A, Erlandsson MC, Andersson KME, Silfverswärd ST, Gay S, Bokarewa MI. Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8 + T Cells in Rheumatoid Arthritis. Front Immunol 2020; 11:1474. [PMID: 32765511 PMCID: PMC7381249 DOI: 10.3389/fimmu.2020.01474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/05/2020] [Indexed: 12/14/2022] Open
Abstract
Objective: Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8+ T cell memory formation through a microRNA (miR) dependent mechanism. Methods: Phenotypes of CD8+ T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry. A microarray analysis was used to screen for differences in miR expression. Sorted CD8+ cells were in vitro stimulated with nicotine and analyzed for transcription of miRs and genes related to memory programming by qPCR. Results: CD27+CD107a−CD8+ T cells, defining a naïve-memory population, had low expression of PD-1. Additionally, the CD27+ population was more frequent in smokers (p = 0.0089). Smokers were recognized by differential expression of eight miRs. Let-7c-5p, let-7d-5p and let-7e-5p, miR-92a-3p, miR-150-5p, and miR-181-5p were up regulated, while miR-3196 and miR-4723-5p were down regulated. These miRs were predicted to target proteins within the FOXO-signaling pathway involved in CD8+ memory programming. Furthermore, miR-92a-3p was differentially expressed in CD8+ cells with naïve-memory predominance. Nicotine exposure of CD8+ cells induced the expression of miR-150-5p and miR-181a-5p in the naïve-memory cells in vitro. Additionally, nicotine exposure inverted the ratio between mRNAs of proteins in the FOXO pathway and their targeting miRs. Conclusions: Smokers have a high prevalence of CD8+ T cells with a naïve-memory phenotype. These cells express a miR profile that interacts with the memory programming conducted through the FOXO pathway.
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Affiliation(s)
- Caroline Wasén
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Caroline Ospelt
- Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.,University of Zurich, Zurich, Switzerland
| | - Alessandro Camponeschi
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Malin C Erlandsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Karin M E Andersson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sofia Töyrä Silfverswärd
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Steffen Gay
- Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
| | - Maria I Bokarewa
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Sahlgrenska University Hospital, Gothenburg, Sweden
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22
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Huang H, Long L, Zhou P, Chapman NM, Chi H. mTOR signaling at the crossroads of environmental signals and T-cell fate decisions. Immunol Rev 2020; 295:15-38. [PMID: 32212344 PMCID: PMC8101438 DOI: 10.1111/imr.12845] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/19/2020] [Indexed: 12/28/2022]
Abstract
The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T-cell development, homeostasis, activation, and effector-cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T-cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T-cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.
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Affiliation(s)
- Hongling Huang
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Lingyun Long
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Equal contribution
| | - Peipei Zhou
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Equal contribution
| | - Nicole M. Chapman
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Hongbo Chi
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
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Zhang Z, Li F, Tian Y, Cao L, Gao Q, Zhang C, Zhang K, Shen C, Ping Y, Maimela NR, Wang L, Zhang B, Zhang Y. Metformin Enhances the Antitumor Activity of CD8 + T Lymphocytes via the AMPK-miR-107-Eomes-PD-1 Pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:2575-2588. [PMID: 32221038 DOI: 10.4049/jimmunol.1901213] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 02/01/2020] [Indexed: 01/04/2023]
Abstract
Metformin has been studied for its anticancer effects by regulating T cell functions. However, the mechanisms through which metformin stimulates the differentiation of memory T cells remain unclear. We found that the frequencies of memory stem and central memory T cells increased for both in peripheral and tumor-infiltrating CD8+ T cells in metformin-treated lung cancer patients compared with those not taking the medication. An in vitro assay showed that metformin promoted the formation of memory CD8+ T cells and enhanced their antiapoptotic abilities. In addition, AMP-activated protein kinase (AMPK) activation decreased microRNA-107 expression, thus enhancing Eomesodermin expression, which suppressed the transcription of PDCD1 in metformin-treated CD8+ T cells. In the CAR-T cell therapy model, metformin also exhibited cytotoxicity-promoting effects that led to decreased tumor growth. Metformin could reprogram the differentiation of CD8+ T cells, which may benefit the clinical therapy of cancer patients by facilitating long-lasting cytotoxic functions.
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Affiliation(s)
- Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Feng Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yonggui Tian
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Ling Cao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qun Gao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chaoqi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Kai Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chunyi Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yu Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | | | - Liping Wang
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Bin Zhang
- Department of Hematology/Oncology, School of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China;
- School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
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24
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Wells AC, Pobezinskaya EL, Pobezinsky LA. Non-coding RNAs in CD8 T cell biology. Mol Immunol 2020; 120:67-73. [PMID: 32085976 PMCID: PMC7093237 DOI: 10.1016/j.molimm.2020.01.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022]
Abstract
CD8 T cells are among the most vigorous soldiers of the immune system that fight viral infections and cancer. CD8 T cell development, maintenance, activation and differentiation are under the tight control of multiple transcriptional and post-transcriptional networks. Over the last two decades it has become clear that non-coding RNAs (ncRNAs), which consist of microRNAs (miRNAs) and long ncRNAs (lncRNAs), have emerged as global biological regulators. While our understanding of the function of specific miRNAs has increased since the discovery of RNA interference, it is still very limited, and the field of lncRNAs is just starting to blossom. Here we will summarize our knowledge on the role of ncRNAs in CD8 T cell biology, including differentiation into memory and exhausted cells.
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Affiliation(s)
- Alexandria C Wells
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, United States.
| | - Elena L Pobezinskaya
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, 01003, United States.
| | - Leonid A Pobezinsky
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, 01003, United States.
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25
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Amado T, Amorim A, Enguita FJ, Romero PV, Inácio D, de Miranda MP, Winter SJ, Simas JP, Krueger A, Schmolka N, Silva-Santos B, Gomes AQ. MicroRNA-181a regulates IFN-γ expression in effector CD8 + T cell differentiation. J Mol Med (Berl) 2020; 98:309-320. [PMID: 32002568 PMCID: PMC7007887 DOI: 10.1007/s00109-019-01865-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 11/29/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022]
Abstract
CD8+ T cells are key players in immunity against intracellular infections and tumors. The main cytokine associated with these protective responses is interferon-γ (IFN-γ), whose production is known to be regulated at the transcriptional level during CD8+ T cell differentiation. Here we found that microRNAs constitute a posttranscriptional brake to IFN-γ expression by CD8+ T cells, since the genetic interference with the Dicer processing machinery resulted in the overproduction of IFN-γ by both thymic and peripheral CD8+ T cells. Using a gene reporter mouse for IFN-γ locus activity, we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8+ T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFN-γ+ CD8+ T cell response and were able to control viral infection significantly more efficiently than control mice. These data collectively establish a novel role for miR-181a in regulating IFN-γ–mediated effector CD8+ T cell responses in vitro and in vivo.
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Affiliation(s)
- Tiago Amado
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Amorim
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Institute of experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Francisco J Enguita
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Paula V Romero
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Daniel Inácio
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Marta Pires de Miranda
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Samantha J Winter
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - J Pedro Simas
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Andreas Krueger
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Nina Schmolka
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. .,Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
| | - Bruno Silva-Santos
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
| | - Anita Q Gomes
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. .,H&TRC Health & Technology Research Center, ESTeSL - Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, Lisbon, Portugal.
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26
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Learning of Signaling Networks: Molecular Mechanisms. Trends Biochem Sci 2020; 45:284-294. [PMID: 32008897 DOI: 10.1016/j.tibs.2019.12.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/28/2019] [Accepted: 12/31/2019] [Indexed: 01/03/2023]
Abstract
Molecular processes of neuronal learning have been well described. However, learning mechanisms of non-neuronal cells are not yet fully understood at the molecular level. Here, we discuss molecular mechanisms of cellular learning, including conformational memory of intrinsically disordered proteins (IDPs) and prions, signaling cascades, protein translocation, RNAs [miRNA and long noncoding RNA (lncRNA)], and chromatin memory. We hypothesize that these processes constitute the learning of signaling networks and correspond to a generalized Hebbian learning process of single, non-neuronal cells, and we discuss how cellular learning may open novel directions in drug design and inspire new artificial intelligence methods.
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27
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Translational Landscape of mTOR Signaling in Integrating Cues Between Cancer and Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1223:69-80. [PMID: 32030685 DOI: 10.1007/978-3-030-35582-1_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental paracrine and autocrine stimuli in tumor microenvironment (TME) constituents. Recently, further efforts have been employed to understand how the mTOR signal transduction mechanisms modulate the sensitivity and resistance to targeted therapies, also for its involvement of mTOR also in modulating angiogenesis and tumor immunity. Indeed, interest in mTOR targeting was increased to improve immune response against cancer and to develop new long-term efficacy strategies, as demonstrated by clinical success of mTOR and immune checkpoint inhibitor combinations. In this chapter, we will describe the role of mTOR in modulating TME elements and the implication in its targeting as a great promise in clinical trials.
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28
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Kim C, Hu B, Jadhav RR, Jin J, Zhang H, Cavanagh MM, Akondy RS, Ahmed R, Weyand CM, Goronzy JJ. Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells. Cell Rep 2019; 25:2148-2162.e5. [PMID: 30463012 PMCID: PMC6371971 DOI: 10.1016/j.celrep.2018.10.074] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/24/2018] [Accepted: 10/19/2018] [Indexed: 01/09/2023] Open
Abstract
Induction of protective vaccine responses, governed by the successful generation of antigen-specific anti-bodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcrip-tome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling path-ways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses. A hallmark of the aging immune system is its failure to induce long-lived memory. Kim et al. report that increased expression of miR-21 in naive T cells from older individuals sustains signaling in the MAPK and AKT-mTORC pathways, disfavoring induction of transcription factor networks involved in memory cell generation.
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Affiliation(s)
- Chulwoo Kim
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Bin Hu
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Rohit R Jadhav
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Jun Jin
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Huimin Zhang
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Mary M Cavanagh
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Rama S Akondy
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Rafi Ahmed
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, USA.
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29
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Abstract
MicroRNAs (miRNAs) are a class of short noncoding RNAs that play critical roles in the regulation of a broad range of biological processes. Like transcription factors, miRNAs exert their effects by modulating the expression of networks of genes that operate in common or convergent pathways. CD8+ T cells are critical agents of the adaptive immune system that provide protection from infection and cancer. Here, we review the important roles of miRNAs in the regulation of CD8+ T cell biology and provide perspectives on the broader emerging principles of miRNA function.
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Affiliation(s)
- John D Gagnon
- Sandler Asthma Basic Research Center, Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA, USA
| | - K Mark Ansel
- Sandler Asthma Basic Research Center, Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA, USA
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30
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Chen Y, Wang W, Chen Y, Tang Q, Zhu W, Li D, Liao L. MicroRNA-19a-3p promotes rheumatoid arthritis fibroblast-like synoviocytes via targeting SOCS3. J Cell Biochem 2019; 120:11624-11632. [PMID: 30854695 DOI: 10.1002/jcb.28442] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 12/02/2018] [Accepted: 12/06/2018] [Indexed: 01/24/2023]
Abstract
Rheumatoid arthritis (RA) is a common chronic autoimmune disease and effective treatment for RA is still lacking. In this study, the regulatory role of miR-19a-3p in RA was investigated. Quantitative polymerase chain reaction analysis of human blood samples showed that the level of miR-19a-3p was significantly lower in the RA patients compared with that in healthy patients (P < 0.05). In RA fibroblast-like synoviocytes (RAFLS), miR-19a-3p and suppressor of cytokine signaling 3 (SOCS3) were also downregulated and upregulated, respectively, compared with those of normal FLS. Transfection of miR-19a-3p mimic in RAFLS inhibited cell proliferation and promoted cell apoptosis. TargetScan identified SOCS3 as a target of miR-19a-3p, which was confirmed by dual-luciferase assay. Western blot indicated that SOCS3 protein level was significantly decreased after miR-19a-3p overexpression. Moreover, SOCS3 silencing through siRNA transfection also enhanced cell proliferation, meanwhile inhibiting RAFLS apoptosis. In addition, SOCS3 overexpression abrogated the effects of miR-19a-3p overexpression on cell proliferation and apoptosis, corroborating that SOCS3 acts as a downstream effector in the miR-19a-3p-mediated function of RAFLS. These findings suggest that miR-19a-3p plays an important role in RA, and the miR-19a-3p/SOCS3 axis may become a potential therapeutic target for RA.
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Affiliation(s)
- Yiyue Chen
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
| | - Wanchun Wang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
| | - You Chen
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
| | - Qi Tang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
| | - Weihong Zhu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
| | - Ding Li
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
| | - Lele Liao
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Furong District, Changsha, Hunan, People's Republic of China
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31
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Labi V, Schoeler K, Melamed D. miR-17∼92 in lymphocyte development and lymphomagenesis. Cancer Lett 2019; 446:73-80. [PMID: 30660648 DOI: 10.1016/j.canlet.2018.12.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/06/2018] [Accepted: 12/31/2018] [Indexed: 01/07/2023]
Abstract
microRNAs (miRNAs) down-modulate the levels of proteins by sequence-specific binding to their respective target mRNAs, causing translational repression or mRNA degradation. The miR-17∼92 cluster encodes for six miRNAs whose target recognition specificities are determined by their distinct sequence. In mice, the four miRNA families generated from the miR-17∼92 cluster coordinate to allow for proper lymphocyte development and effective adaptive immune responses following infection or immunization. Lymphocyte development and homeostasis rely on tight regulation of PI3K signaling to avoid autoimmunity or immunodeficiency, and the miR-17∼92 miRNAs appear as key mediators to appropriately tune PI3K activity. On the other hand, in lymphoid tumors overexpression of the miR-17∼92 miRNAs is a common oncogenic event. In this review, we touch on what we have learned so far about the miR-17∼92 miRNAs, particularly with respect to their role in lymphocyte development, homeostasis and pathology.
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Affiliation(s)
- Verena Labi
- Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, 6020, Austria.
| | - Katia Schoeler
- Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, 6020, Austria
| | - Doron Melamed
- Department of Immunology, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
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32
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He W, Xu J, Huang Z, Zhang J, Dong L. MiRNAs in cancer therapy: focusing on their bi-directional roles. ACTA ACUST UNITED AC 2019. [DOI: 10.1186/s41544-019-0005-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Chen S, Wang Y, Qin H, Lin J, Xie L, Chen S, Liang J, Xu J. Downregulation of miR-633 activated AKT/mTOR pathway by targeting AKT1 in lupus CD4+ T cells. Lupus 2019; 28:510-519. [PMID: 30760089 DOI: 10.1177/0961203319829853] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Background Accumulating evidence suggests that the AKT/mTOR pathway plays an important role in the pathogenesis of systemic lupus erythematosus (SLE) through activating T cells, and there are few studies looking into the role of microRNA (miRNAs) in the mechanism. We first found that miR-633 expression in CD4+T cells of SLE patients was significantly reduced. Objective To investigate the role of miR-633 in the AKT/mTOR pathway in lupus CD4+T cells. Methods Samples of 17 SLE cases and 16 healthy controls were collected to detect the expression of miR-633, AKT1, mTOR mRNA and proteins by quantitative polymerase chain reaction (qPCR) and Western-blot, respectively. To determine whether AKT1 is a direct target of miR-633, a luciferase assay was performed. In vitro, AKT1 siRNA, miR-633 mimics/inhibitors or negative controls were transfected to Jurkat cells, human primary CD4+T cells and lupus CD4+T cells. RNA and proteins were extracted after 48 h, and levels of AKT/mTOR pathway markers and downstream multiple cytokines were detected by qPCR or Western-blot. Results In SLE patients, the miR-633 levels in CD4+T cells were significantly decreased and negatively correlated with SLEDAI. AKT1, mTOR mRNA and proteins were all up-regulated. The degree of downregulation of miR-633 was correlated negatively with AKT1 mRNA. The luciferase assay proved that AKT1 is a direct target of miR-633. In Jurkat and lupus CD4+T cells, overexpression of miR-633 could result in lower levels of AKT1 and mTOR. Inhibition of miR-633 expression in primary CD4+T cells caused reverse effects, and protein levels of p-AKT, p-mTOR, and p-S6RP increased. Moreover, among various cytokines, the expression of IL-4, IL-17, and IFN-γ mRNA was raised. Conclusion Our study suggests that miR-633 deletion can activate the AKT/mTOR pathway by targeting AKT1 to participate in the pathogenesis of SLE.
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Affiliation(s)
- S Chen
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Y Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - H Qin
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - J Lin
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - L Xie
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - S Chen
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - J Liang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - J Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Dermatology, Shanghai, China
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Rezaei N, Talebi F, Ghorbani S, Rezaei A, Esmaeili A, Noorbakhsh F, Hakemi MG. MicroRNA-92a Drives Th1 Responses in the Experimental Autoimmune Encephalomyelitis. Inflammation 2019; 42:235-245. [PMID: 30411211 DOI: 10.1007/s10753-018-0887-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dysregulation of microRNAs (miRNAs) has been linked to the progress of a number of autoimmune diseases including multiple sclerosis (MS), and its animal model, experimental autoimmune encephalomyelitis (EAE). IFN-γ-producing Th1 cells are major players in MS/EAE pathogenesis. It is known that differentiation of T cells towards the Th1 phenotype is influenced by various factors including miRNAs. The miR-92a shows substantial upregulation in MS; however, little is known about its role in the development of autoimmune and inflammatory responses. Herein, we investigated the role of miR-92a in the pathogenesis of MS, focusing on its potential effects on differentiation of Th1 cells. The expression levels of miR-92a were assessed in the spinal cord tissues and splenocytes from mice with EAE using real-time RT-PCR. Next, using transfection with miR-92a mimic sequences, the potential involvement of miR-92a in Th1 polarization was investigated by flow cytometric analysis. Moreover, the expression levels of miR-92a targets were explored in spinal cord tissues of EAE mice. miR-92a expression was enhanced in mouse spinal cord samples at the peak of EAE disease. Overexpression of miR-92a in splenocytes led to increased differentiation of Th1 cells compared with cells transfected with negative control sequences. Enhanced miR-92a expression was accompanied by reduced expression TSC1 or DUSP10, predicted miR-92a targets, in EAE spinal cords. Our data point to a potential role for miR-92a in neuroinflammatory responses in EAE. Our results indicate that miR-92a might affect Th1 differentiation, likely due to downregulation of TSC1 and DUSP10.
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Affiliation(s)
- Nahid Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farideh Talebi
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Ghorbani
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Gustafson CE, Cavanagh MM, Jin J, Weyand CM, Goronzy JJ. Functional pathways regulated by microRNA networks in CD8 T-cell aging. Aging Cell 2019; 18:e12879. [PMID: 30488559 PMCID: PMC6351841 DOI: 10.1111/acel.12879] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/26/2018] [Accepted: 10/21/2018] [Indexed: 12/13/2022] Open
Abstract
One of the most prominent immunological changes during human aging is the alteration in CD8 T-cell subset distribution, predominated by a loss of naïve CD8 T cells. The molecular mechanisms that contribute to the loss of naïve CD8 T-cells during aging remain unclear. Considering that many CD8 T-cell functions are influenced by microRNAs (miRNAs), we explored miRNA expression profiling to identify novel dysfunctions that contribute to naïve CD8 T-cell loss during aging. Here, we describe age-dependent miRNA expression changes in naïve, central memory, and effector memory CD8 T-cell subsets. Changes in old naïve CD8 T-cells partially resembled those driven by an underlying shift in cellular differentiation toward a young central memory phenotype. Pathways enriched for targets of age-dependent miRNAs included FOXO1, NF-κB, and PI3K-AKT signaling. Transcriptome analysis of old naïve CD8 T-cells yielded corresponding patterns that correlated to those seen with reduced FOXO1 or altered NF-κB activities. Of particular interest, IL-7R expression, controlled by FOXO1 signaling, declines on naïve CD8 T cells with age and directly correlates with the frequencies of naïve CD8 T cells. Thus, age-associated changes in miRNA networks may ultimately contribute to the failure in CD8 T-cell homeostasis exemplified by the loss in naïve cells.
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Affiliation(s)
- Claire E Gustafson
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Mary M Cavanagh
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Jun Jin
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
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36
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Yin LB, Song CB, Zheng JF, Fu YJ, Qian S, Jiang YJ, Xu JJ, Ding HB, Shang H, Zhang ZN. Elevated Expression of miR-19b Enhances CD8 + T Cell Function by Targeting PTEN in HIV Infected Long Term Non-progressors With Sustained Viral Suppression. Front Immunol 2019; 9:3140. [PMID: 30687333 PMCID: PMC6338066 DOI: 10.3389/fimmu.2018.03140] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 12/19/2018] [Indexed: 11/13/2022] Open
Abstract
Human immunodeficiency virus (HIV)-infected long-term non-progressors (LTNPs) are of particular importance because of their unique disease progression characteristics. Defined by the maintenance of normal CD4+T cells after more than 8 years of infection, these LTNPs are heterogeneous. Some LTNPs exhibit ongoing viral production, while others do not and are able to control viral production. The underlying basis for this heterogeneity has not been clearly elucidated. In this study, the miRNA expression profiles of LTNPs were assessed. The levels of microRNA-19b (miR-19b) were found to be significantly increased in peripheral blood mononuclear cells of LTNPs with lower rather than higher viral load. We made clear that miR-19b may regulate CD8+T cell functions in HIV infection, which has not been addressed before. Overexpression of miR-19b promoted CD8+T cell proliferation, as well as interferon-γ and granzyme B expression, while inhibiting CD8+T cells apoptosis induced by anti-CD3/CD28 stimulation. The target of miR-19b was found to be the "phosphatase and tensin homolog", which regulates CD8+T cells function during HIV infections. Furthermore, we found that miR-19b can directly inhibit viral production in in-vitro HIV infected T cells. These results highlight the importance of miR-19b to control viral levels, which facilitate an understanding of human immunodeficiency virus pathogenesis and provide potential targets for improved immune intervention.
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Affiliation(s)
- Lin-Bo Yin
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Cheng-Bo Song
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Jie-Fu Zheng
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Ya-Jing Fu
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shi Qian
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Yong-Jun Jiang
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Jun-Jie Xu
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Hai-Bo Ding
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Hong Shang
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Zi-Ning Zhang
- NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China.,Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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37
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Zhang T, Zhang Z, Li F, Ping Y, Qin G, Zhang C, Zhang Y. miR-143 Regulates Memory T Cell Differentiation by Reprogramming T Cell Metabolism. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:2165-2175. [PMID: 30150287 DOI: 10.4049/jimmunol.1800230] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 07/28/2018] [Indexed: 12/31/2022]
Abstract
MicroRNAs are an important regulator for T cell immune response. In this study, we aimed to identify microRNAs with the potential to regulate T cell differentiation. The influence of miR-143 on differentiation and function of CD8+ T cells from healthy donors were detected, and it was found that miR-143 overexpression could significantly increase the differentiation of central memory T (Tcm) CD8+ cells, decrease cell apoptosis, and increase proinflammatory cytokine secretion. Furthermore, the specific killing of HER2-CAR T cells against esophageal cancer cell line TE-7 was enhanced by miR-143 overexpression. Glucose transporter 1 (Glut-1) was identified as the critical target gene of miR-143 in the role of T cell regulation. By inhibition Glut-1, miR-143 inhibited glucose uptake and glycolysis in T cell to regulated T cell differentiation. Tcm cell populations were also suppressed in parallel with the downregulation of miR-143 in tumor tissues from 13 patients with esophagus cancer. IDO and its metabolite kynurenine in the tumor microenvironment were screened as an upstream regulator of miR-143. IDO small interfering RNA significantly increased the expression of miR-143 and Tcm cell population. In conclusion, our results show that miR-143 enhanced antitumor effects of T cell by promoting memory T cell differentiation and metabolism reprogramming through Glut-1. Our findings will encourage the development of new strategies targeting miR-143 in both cancer cells and T cells.
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Affiliation(s)
- Tengfei Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Feng Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yu Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Guohui Qin
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chaoqi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China;
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China; and
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
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38
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Giri BR, Mahato RI, Cheng G. Roles of microRNAs in T cell immunity: Implications for strategy development against infectious diseases. Med Res Rev 2018; 39:706-732. [PMID: 30272819 DOI: 10.1002/med.21539] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 12/19/2022]
Abstract
T cell immunity plays a vital role in pathogen infections. MicroRNA (miRNAs) are small, single-stranded noncoding RNAs that regulate T cell immunity by targeting key transcriptional factors, signaling proteins, and cytokines associated with T cell activation, differentiation, and function. The dysregulation of miRNA expression in T cells may lead to specific immune responses and can provide new therapeutic opportunities against various infectious diseases. Here, we summarize recent studies that focus on the roles of miRNAs in T cell immunity and highlight miRNA functions in prevalent infectious diseases. Additionally, we also provide insights into the functions of extracellular vesicle miRNAs and attempt to delineate the mechanism of miRNA sorting into extracellular vesicles and their immunomodulatory functions. Moreover, methodologies and strategies for miRNA delivery against infectious diseases are summarized. Finally, potential strategies for miRNA-based therapies are proposed.
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Affiliation(s)
- Bikash R Giri
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Guofeng Cheng
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
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39
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Increased expression of microRNAs, miR-20a and miR-326 in PBMCs of patients with type 1 diabetes. Mol Biol Rep 2018; 45:1973-1980. [PMID: 30194557 DOI: 10.1007/s11033-018-4352-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 08/31/2018] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder which is characterized by autoimmune attack on β cells of pancreas and lack of insulin. The involvement of microRNAs (miRNAs) in the development of immune system and their differential expression in various autoimmune diseases including T1D have been well established. In this study, the association between expression levels of miR-20a, miR-326 and T1D were evaluated. The expression levels of miR-20a and miR-326 were measured in the PBMCs of 21 T1D patients and 16 healthy controls using qPCR method. In silico analysis was also performed on targetome of miR-20a and miR-326. Both miR-20a (p value: 0.015) and miR-326 (p value: 0.005) were upregulated in the PBMCs of T1D patients compared to healthy controls. Furthermore, different dysregulated miR326-mRNA and miR20a-mRNA interactions were also suggested using integrative computational analysis. The expression level of miR-20a and miR-326 indicates significant association with T1D which suggests the possible regulatory effects of these non-coding RNAs in T1D.
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40
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Hirschberger S, Hinske LC, Kreth S. MiRNAs: dynamic regulators of immune cell functions in inflammation and cancer. Cancer Lett 2018; 431:11-21. [PMID: 29800684 DOI: 10.1016/j.canlet.2018.05.020] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/14/2018] [Accepted: 05/15/2018] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs), small noncoding RNA molecules, have emerged as important regulators of almost all cellular processes. By binding to specific sequence motifs within the 3'- untranslated region of their target mRNAs, they induce either mRNA degradation or translational repression. In the human immune system, potent miRNAs and miRNA-clusters have been discovered, that exert pivotal roles in the regulation of gene expression. By targeting cellular signaling hubs, these so-called immuno-miRs have fundamental regulative impact on both innate and adaptive immune cells in health and disease. Importantly, they also act as mediators of tumor immune escape. Secreted by cancer cells and consecutively taken up by immune cells, immuno-miRs are capable to influence immune functions towards a blunted anti-tumor response, thus shaping a permissive tumor environment. This review provides an overview of immuno-miRs and their functional impact on individual immune cell entities. Further, implications of immuno-miRs in the amelioration of tumor surveillance are discussed.
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Affiliation(s)
- Simon Hirschberger
- Department of Anesthesiology, University Hospital, LMU Munich, Germany; Walter-Brendel-Center of Experimental Medicine, LMU Munich, Germany
| | | | - Simone Kreth
- Department of Anesthesiology, University Hospital, LMU Munich, Germany; Walter-Brendel-Center of Experimental Medicine, LMU Munich, Germany.
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41
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Chen Z, Stelekati E, Kurachi M, Yu S, Cai Z, Manne S, Khan O, Yang X, Wherry EJ. miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb. Cell Rep 2018; 20:2584-2597. [PMID: 28903040 DOI: 10.1016/j.celrep.2017.08.060] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 06/09/2017] [Accepted: 08/01/2017] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs play an important role in T cell responses. However, how microRNAs regulate CD8 T cell memory remains poorly defined. Here, we found that miR-150 negatively regulates CD8 T cell memory in vivo. Genetic deletion of miR-150 disrupted the balance between memory precursor and terminal effector CD8 T cells following acute viral infection. Moreover, miR-150-deficient memory CD8 T cells were more protective upon rechallenge. A key circuit whereby miR-150 repressed memory CD8 T cell development through the transcription factor c-Myb was identified. Without miR-150, c-Myb was upregulated and anti-apoptotic targets of c-Myb, such as Bcl-2 and Bcl-xL, were also increased, suggesting a miR-150-c-Myb survival circuit during memory CD8 T cell development. Indeed, overexpression of non-repressible c-Myb rescued the memory CD8 T cell defects caused by overexpression of miR-150. Overall, these results identify a key role for miR-150 in memory CD8 T cells through a c-Myb-controlled enhanced survival circuit.
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Affiliation(s)
- Zeyu Chen
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
| | - Erietta Stelekati
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
| | - Makoto Kurachi
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
| | - Sixiang Yu
- Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Zhangying Cai
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; College of Life Sciences, Peking University, Beijing, China
| | - Sasikanth Manne
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
| | - Omar Khan
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
| | - Xiaolu Yang
- Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - E John Wherry
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
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42
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Ban YH, Oh SC, Seo SH, Kim SM, Choi IP, Greenberg PD, Chang J, Kim TD, Ha SJ. miR-150-Mediated Foxo1 Regulation Programs CD8 + T Cell Differentiation. Cell Rep 2018; 20:2598-2611. [PMID: 28903041 DOI: 10.1016/j.celrep.2017.08.065] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 06/30/2017] [Accepted: 08/21/2017] [Indexed: 01/01/2023] Open
Abstract
MicroRNA (miR)-150 is a developmental regulator of several immune-cell types, but its role in CD8+ T cells is largely unexplored. Here, we show that miR-150 regulates the generation of memory CD8+ T cells. After acute virus infection, miR-150 knockout (KO) mice exhibited an accelerated differentiation of CD8+ T cells into memory cells and improved production of effector cytokines. Additionally, miR-150 KO CD8+ T cells displayed an enhanced recall response and improved protection against infections with another virus and bacteria. We found that forkhead box O1 (Foxo1) and T cell-specific transcription factor 1 (TCF1) are upregulated during the early activation phase in miR-150 KO CD8+ T cells and that miR-150 directly targets and suppresses Foxo1. These results suggest that miR-150-mediated suppression of Foxo1 regulates the balance between effector and memory cell differentiation, which might aid in the development of improved vaccines and T cell therapeutics.
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Affiliation(s)
- Young Ho Ban
- Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Se-Chan Oh
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Sang-Hwan Seo
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Seok-Min Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - In-Pyo Choi
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Philip D Greenberg
- Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195, USA
| | - Jun Chang
- Division of Life & Pharmaceutical Sciences, Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul 03760, Korea
| | - Tae-Don Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea.
| | - Sang-Jun Ha
- Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea.
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43
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Koenecke C, Krueger A. MicroRNA in T-Cell Development and T-Cell Mediated Acute Graft-Versus-Host Disease. Front Immunol 2018; 9:992. [PMID: 29867969 PMCID: PMC5949326 DOI: 10.3389/fimmu.2018.00992] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/20/2018] [Indexed: 12/21/2022] Open
Abstract
Acute graft-versus-host disease (GvHD) is still a major cause of treatment-related mortality after allogeneic stem cell transplantation. Allo-antigen recognition of donor T cells after transplantation account for the onset and persistence of this disease. MicroRNAs (miRNAs) are molecular regulators involved in numerous processes during T-cell development, homeostasis, and activation. Thus, miRNAs also contribute to pathological T-cell function during GvHD. Given their capacity of fine-tuning T-cell function, miRNAs have emerged as promising therapeutic targets to curtail acute GvHD, but simultaneously maintain T-cell-mediated graft-versus-tumor effects. Here, we review the role of key miRNAs contributing to the pathophysiology of GvHD. We focus on those miRNAs acting in T cells and for which a role in GvHD has been established in preclinical models. Finally, we provide an outlook for clinical application of this new therapeutic target for GvHD prevention and treatment.
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Affiliation(s)
- Christian Koenecke
- Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Andreas Krueger
- Institute for Molecular Medicine, Goethe-University Frankfurt, Frankfurt am Main, Germany
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44
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Inácio DP, Amado T, Silva-Santos B, Gomes AQ. Control of T cell effector functions by miRNAs. Cancer Lett 2018; 427:63-73. [PMID: 29679611 DOI: 10.1016/j.canlet.2018.04.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/23/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
The differentiation of effector T cells is a tightly regulated process that relies on the selective expression of lineage-defining master regulators that orchestrate unique transcriptional programs, including the production of distinct sets of effector cytokines. miRNAs are post-transcriptional regulators that are now viewed as critical players in these gene expression networks and help defining cell identity and function. This review summarises the role of individual miRNAs in the regulation of the differentiation of effector T cell subsets, including CD4+ T helper cells, cytotoxic CD8+ T cells and innate-like NKT cells. Moreover, we refer to miRNAs that have been identified to affect simultaneously two or more effector T cell populations, impacting on the balance between effector T cells in vivo, thus constituting potential biomarkers or targets for therapies aiming at boosting immunity or controlling autoimmunity.
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Affiliation(s)
- Daniel P Inácio
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Tiago Amado
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Bruno Silva-Santos
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Anita Q Gomes
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal; Escola Superior de Tecnologia da Saúde de Lisboa, 1990-096, Lisboa, Portugal.
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45
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Diverse functions of miR-17-92 cluster microRNAs in T helper cells. Cancer Lett 2018; 423:147-152. [PMID: 29499238 DOI: 10.1016/j.canlet.2018.02.035] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/15/2018] [Accepted: 02/19/2018] [Indexed: 12/24/2022]
Abstract
T helper (Th) cells are critically involved in adaptive immune responses against various pathogens. In contrast, dysregulated T helper cell responses are associated with a variety of diseases, including autoimmunity, allergies, and cancer. Differentiation of naïve CD4+ T cells into effector T helper cell subsets, including Th1, Th2, Th17, Treg, and T follicular helper (Tfh), requires precise dosing of signaling molecules and transcription factors. MicroRNAs (miRNAs), which are small endogenously expressed RNAs that regulate gene expression, play important roles in these processes. The miR-17-92 cluster, a miRNA polycistron also known as oncomiR-1, has emerged as a central integrator of gene expression events that govern T helper cell differentiation pathways. The complexity of miR-17-92-mediated gene regulation lies in the nature of this miRNA cluster, which consists of six different miRNAs. Individual miR-17-92 miRNAs, albeit initially transcribed as one transcript, can have cooperative or opposing effects on biological processes. Therefore, a better understanding of the molecular regulation of miR-17-92 and its downstream networks will provide important insights into T helper cell differentiation and diversity that may be harnessed for the design of advanced T cell-targeting therapies.
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46
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Alunni-Fabbroni M, Majunke L, Trapp EK, Tzschaschel M, Mahner S, Fasching PA, Fehm T, Schneeweiss A, Beck T, Lorenz R, Friedl TWP, Janni W, Rack B. Whole blood microRNAs as potential biomarkers in post-operative early breast cancer patients. BMC Cancer 2018; 18:141. [PMID: 29409452 PMCID: PMC5802058 DOI: 10.1186/s12885-018-4020-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 01/22/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND microRNAs (miRNAs) are considered promising cancer biomarkers, showing high reliability, sensitivity and stability. Our study aimed to identify associations between whole blood miRNA profiles, presence of circulating tumor cells (CTCs) and clinical outcome in post-operative early breast cancer patients (EBC) to assess the utility of miRNAs as prognostic markers in this setting. METHOD A total of 48 post-operative patients, recruited in frame of the SUCCESS A trial, were included in this retrospective study and tested with a panel of 8 miRNAs (miR-10b, -19a, - 21, - 22, -20a, - 127, - 155, -200b). Additional 17 female healthy donors with no previous history of cancer were included in the study as negative controls. Blood samples were collected at different time points (pre-adjuvant therapy, post-adjuvant therapy, 2 years follow up), total RNA was extracted and the relative concentration of each miRNA was measured by quantitative PCR and compared in patients stratified on blood collection time or CTC detection. Furthermore, we compared miRNA profiles of patients, for each time point separately, and healthy donors. CTCs were visualized and quantified with immunocytochemistry analysis. Data were analyzed using non-parametric statistical tests. RESULTS In our experimental system, miR-19a, miR-22 and miR-127 showed the most promising results, differentiating patients at different time points and from healthy controls, while miR-20a, miR-21 and miR-200b did not show any difference among the different groups. miR-10b and miR-155 were never detectable in our experimental system. With respect to patients' clinical characteristics, we found a significant correlation between miR-200b and lymph node status and between miR-20a and tumor type. Furthermore, miR-127 correlated with the presence of CTCs. Finally, we found a borderline significance between Progression Free Survival and miR-19a levels. CONCLUSIONS This pilot study suggests that profiling whole blood miRNAs could help to better stratify post-operative EBC patients without any sign of metastasis to prevent later relapse or metastatic events.
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Affiliation(s)
- Marianna Alunni-Fabbroni
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany. .,Laboratory for Experimental Radiology, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital, Marchioninistr. 15, 81377, Munich, Germany.
| | - Leonie Majunke
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - Elisabeth K Trapp
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany.,Department of Gynecology and Obstetrics, Medical University of Graz, Graz, Austria
| | - Marie Tzschaschel
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany.,Department of Gynecology and Obstetrics, Medical University of Graz, Graz, Austria
| | - Sven Mahner
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, Erlangen University Hospital, Erlangen, Germany
| | - Tanja Fehm
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany
| | - Andreas Schneeweiss
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Beck
- RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Ralf Lorenz
- Gemeinschaftspraxis Lorenz / Hecker / Wesche, Braunschweig, Germany
| | - Thomas W P Friedl
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Brigitte Rack
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany.,Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
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47
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The Secrets of T Cell Polarization. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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48
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Wang S, Liu P, Yang P, Zheng J, Zhao D. Peripheral blood microRNAs expression is associated with infant respiratory syncytial virus infection. Oncotarget 2017; 8:96627-96635. [PMID: 29228557 PMCID: PMC5722509 DOI: 10.18632/oncotarget.19364] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 06/27/2017] [Indexed: 12/30/2022] Open
Abstract
MicroRNAs respond to the inflammatory responses induced by RNA virus infection. In this study, we investigated the specific microRNA profile in the peripheral blood of infants infected with respiratory syncytial virus (RSV). Blood specimens were analyzed using microRNA microarrays, followed by quantitative RT-PCR. A specific microRNA profile in the peripheral blood of RSV-infected infants was identified for the first time. MiR-106b-5p, miR-20b-5p, and miR-342-3p were upregulated, while miR-320e, miR-320d, miR-877-5p, miR-122-5p, and miR-92b-5p were downregulated. Pathway analysis indicated that the dysregulated microRNAs were involved in inflammatory and immune responses, including Wnt, TGF-β, insulin, and T and B cell receptor signaling. These results demonstrate that RSV infection associates with a distinct microRNA fingerprint and suggest that RSV induces inflammatory responses in infants.
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Affiliation(s)
- Shouyi Wang
- Department of Pediatrics, Children’s Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Pin Liu
- Department of Pediatrics, Children’s Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Pu Yang
- Department of Pediatrics, Children’s Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Junwen Zheng
- Department of Pediatrics, Children’s Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Dongchi Zhao
- Department of Pediatrics, Children’s Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
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49
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Wells AC, Daniels KA, Angelou CC, Fagerberg E, Burnside AS, Markstein M, Alfandari D, Welsh RM, Pobezinskaya EL, Pobezinsky LA. Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells. eLife 2017; 6. [PMID: 28737488 PMCID: PMC5550279 DOI: 10.7554/elife.26398] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 07/21/2017] [Indexed: 12/14/2022] Open
Abstract
The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses. DOI:http://dx.doi.org/10.7554/eLife.26398.001
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Affiliation(s)
- Alexandria C Wells
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
| | - Keith A Daniels
- Department of Pathology, University of Massachusetts Medical School, Worcester, United States
| | - Constance C Angelou
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
| | - Eric Fagerberg
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
| | - Amy S Burnside
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
| | - Michele Markstein
- Department of Biology, University of Massachusetts, Amherst, United States
| | - Dominique Alfandari
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
| | - Raymond M Welsh
- Department of Pathology, University of Massachusetts Medical School, Worcester, United States
| | - Elena L Pobezinskaya
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
| | - Leonid A Pobezinsky
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
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50
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Moffett HF, Cartwright ANR, Kim HJ, Godec J, Pyrdol J, Äijö T, Martinez GJ, Rao A, Lu J, Golub TR, Cantor H, Sharpe AH, Novina CD, Wucherpfennig KW. The microRNA miR-31 inhibits CD8 + T cell function in chronic viral infection. Nat Immunol 2017; 18:791-799. [PMID: 28530712 PMCID: PMC5753758 DOI: 10.1038/ni.3755] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 04/27/2017] [Indexed: 12/13/2022]
Abstract
During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8+ T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection.
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Affiliation(s)
- Howell F Moffett
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Adam N R Cartwright
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Hye-Jung Kim
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Jernej Godec
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Jason Pyrdol
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Tarmo Äijö
- Department of Information and Computer Science, Aalto University School of Science, Aalto, Finland
| | - Gustavo J Martinez
- La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - Anjana Rao
- La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
| | - Jun Lu
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Todd R Golub
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Harvey Cantor
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Arlene H Sharpe
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Carl D Novina
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kai W Wucherpfennig
- Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
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