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Barthels DA, House RV, Gelhaus HC. The immune response to Francisella tularensis. Front Microbiol 2025; 16:1549343. [PMID: 40351308 PMCID: PMC12062900 DOI: 10.3389/fmicb.2025.1549343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/24/2025] [Indexed: 05/14/2025] Open
Abstract
Francisella tularensis (Ft) is a Gram negative intracellular bacterial pathogen, commonly transmitted via arthropod bites, but is most lethal when contracted via inhalation. The nature of a Gram-negative intracellular pathogen presents unique challenges to the mammalian immune response, unlike more common viral pathogens and extracellular bacterial pathogens. The current literature on Ft involves numerous variables, including the use of differing research strains and variation in animal models. This review aims to consolidate much of the recent literature on Ft to suggest promising research to better understand the complex immune response to this bacterium.
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Affiliation(s)
- Derek A. Barthels
- Department of Biology, Life Sciences Research Center, United States Air Force Academy, Colorado Springs, CO, United States
- National Research Council Research Associateships Program, Washington, DC, United States
| | - Robert V. House
- Dr. RV House LLC, Harpers Ferry, WV, United States
- Appili Therapeutics, Halifax, NS, Canada
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Lv M, Jia Y, Dong J, Wu S, Ying H. The landscape of decidual immune cells at the maternal-fetal interface in parturition and preterm birth. Inflamm Res 2025; 74:44. [PMID: 40038160 PMCID: PMC11880140 DOI: 10.1007/s00011-025-02015-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/13/2025] [Accepted: 02/19/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Parturition is similar to an inflammatory response in which resident and infiltrating immune cells release cytokines and chemokines into the maternal-fetal interface, promoting expulsion of the fetus from the mother. The untimely activation of these inflammatory pathways can result in preterm labor. The maternal-fetal interface is composed mainly of decidual tissue and placental villous space. OBJECTIVE The objective of this review is to examine the role and mechanisms of decidual immune cells during parturition and preterm birth. A deeper understanding of decidual immune cells at the maternal-fetal interface could provide significant insight into parturition and preterm birth pathogenesis. METHODS We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing decidual immune cells, parturition and preterm birth up to July 2024 and combined with studies found in the reference lists of the included studies. RESULTS Decidual neutrophils release inflammatory mediators that facilitate parturition. The M1/M2 ratio of decidual macrophages increases among preterm birth population. Mast cells may cause uterine contractions. In parturition and preterm birth, there is an increase in CD56dimCD16+ natural killer cells and immature dendritic cells. The increase of Th1/Th2 and Th17/Treg cells leads to preterm birth. Women with preterm birth had a higher proportion of decidual B cells. ILC2 can help protect the steady-state environment at the maternal-fetal interface. The activation of invariant NKT cells plays an important role in inflammation-induced preterm birth. These decidual immune cells communicate with each other. The development of sequencing technology enables a more in-depth study of decidual immune cells. CONCLUSION The dynamic balance of the maternal-fetal immune microenvironment plays a crucial role in maintaining human pregnancy and in the initiation of delivery. A deep understanding of the mechanism of decidual immune dysfunction is crucial for understanding the pathogenesis of preterm birth.
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Affiliation(s)
- Mu Lv
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200092, China
| | - Yuanhui Jia
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200092, China
| | - Jiaqi Dong
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200092, China
| | - Shengyu Wu
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200092, China
| | - Hao Ying
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200092, China.
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Wang Q, Yu M, Zhang S. The characteristics of the tumor immune microenvironment in colorectal cancer with different MSI status and current therapeutic strategies. Front Immunol 2025; 15:1440830. [PMID: 39877377 PMCID: PMC11772360 DOI: 10.3389/fimmu.2024.1440830] [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: 05/30/2024] [Accepted: 12/16/2024] [Indexed: 01/31/2025] Open
Abstract
Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.
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Affiliation(s)
- Qingzhe Wang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Yu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shuang Zhang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Qian Y, Zhao J, Wu H, Kong X. Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury. Arch Toxicol 2025; 99:115-126. [PMID: 39395921 DOI: 10.1007/s00204-024-03886-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China
| | - Jie Zhao
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China.
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Xu Z, Yang F, Zheng L. Uncovering the dual roles of peripheral immune cells and their connections to brain cells in stroke and post-stroke stages through single-cell sequencing. Front Neurosci 2024; 18:1443438. [PMID: 39633897 PMCID: PMC11614781 DOI: 10.3389/fnins.2024.1443438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 10/24/2024] [Indexed: 12/07/2024] Open
Abstract
Ischemic stroke is a cerebrovascular disease that affects the blood vessels and the blood supply to the brain, making it the second leading cause of death worldwide. Studies suggest that immune cells play a dual role during the inflammatory and recovery phases of stroke. However, in-depth investigations of specific cell subtypes and their differentiation trajectories remain to be elucidated. In this review, we highlight the application of single-cell RNA sequencing (scRNA-seq) for the unbiased identification of cell heterogeneity in brain and peripheral blood mononuclear cells (PBMCs) during and after a stroke. Our goal is to explore the phenotypic landscape of cells with different roles in this context. Specifically, we provide an overview of the roles, cell surface markers, immune cell-released cytokines, and intercellular interactions identified in major immune cells during and after stroke, as identified by different technologies. Additionally, we summarize the connection between immune cells in peripheral blood and the brain via their differentiation trajectories. By synthesizing the application of scRNA-seq in the combined analysis of PBMCs and brain tissue at higher sampling frequencies, we aim to unveil the dual role of peripheral immune cells, which could facilitate the development of new treatment strategies for ischemic stroke.
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Affiliation(s)
- Zheng Xu
- Department of Neurology, Southern University of Sciences and Technology Yantian Hospital, Shenzhen, China
- Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Fan Yang
- Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Lifang Zheng
- Department of Neurology, Southern University of Sciences and Technology Yantian Hospital, Shenzhen, China
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Mori T, Yoshio S, Kakazu E, Kanto T. Active role of the immune system in metabolic dysfunction-associated steatotic liver disease. Gastroenterol Rep (Oxf) 2024; 12:goae089. [PMID: 39411101 PMCID: PMC11479709 DOI: 10.1093/gastro/goae089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/19/2024] [Accepted: 09/10/2024] [Indexed: 10/19/2024] Open
Abstract
Non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a complex multifactorial disease that progresses from steatohepatitis (MASH) to liver cirrhosis and liver cancer. Recent research has revealed that crosstalk between innate immune cells and hepatic parenchymal and non-parenchymal cells is involved in the pathogenesis of liver disease in MASLD/MASH. Of particular importance, novel inflammatory mechanisms, including macrophage diversity, neutrophil NETosis, B-cell biology, auto-reactive T cells, unconventional T cells, and dendritic cell-T cell interactions, are considered key drivers for disease progression. These mechanisms and factors are potential targets for the therapeutic intervention of MASLD/MASH. In this review, we focus on recent discoveries related to liver inflammation and discuss the role of innate immune cell subsets in MASLD/MASH.
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Affiliation(s)
- Taizo Mori
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Sachiyo Yoshio
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Eiji Kakazu
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Tatsuya Kanto
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
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Park KJ, Kim TO, Cho YN, Jin HM, Jo YG, Shin HJ, Kho BG, Kee SJ, Park YW. Deficiency and dysfunctional roles of natural killer T cells in patients with ARDS. Front Immunol 2024; 15:1433028. [PMID: 39281681 PMCID: PMC11392733 DOI: 10.3389/fimmu.2024.1433028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 08/14/2024] [Indexed: 09/18/2024] Open
Abstract
Objective Acute respiratory distress syndrome (ARDS) presents a global health challenge, characterized by significant morbidity and mortality. However, the role of natural killer T (NKT) cells in human ARDS remains poorly understood. Therefore, this study explored the numerical and functional status of NKT cells in patients with ARDS, examining their clinical relevance and interactions with macrophages and fibroblasts during various stages of the syndrome. Methods Peripheral blood from 40 ARDS patients and 30 healthy controls was analyzed, with paired samples of peripheral blood and bronchoalveolar lavage fluid (BALF) from seven ARDS patients. We measured levels of NKT cells, cytokines, CD69, programmed death-1 (PD-1), and annexin-V using flow cytometry, and extracellular matrix (ECM) protein expression using real-time PCR. Results ARDS patients exhibited decreased circulating NKT cells with elevated CD69 expression and enhanced IL-17 production. The reduction in NKT cells correlated with PaO2/FiO2 ratio, albumin, and C-reactive protein levels. Proliferative responses to α-galactosylceramide (α-GalCer) were impaired, and co-culturing NKT cells with monocytes or T cells from ARDS patients resulted in a reduced α-GalCer response. Increased and activated NKT cells in BALF induced proinflammatory cytokine release by macrophages and ECM protein expression in fibroblasts. Conclusion ARDS is associated with a numerical deficiency but functional activation of circulating NKT cells, showing impaired responses to α-GalCer and altered interactions with immune cells. The increase in NKT cells within BALF suggests their role in inducing inflammation and remodeling/fibrosis, highlighting the potential of targeting NKT cells as a therapeutic approach for ARDS.
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Affiliation(s)
- Ki-Jeong Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Tae-Ok Kim
- Department of Pulmonology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Young-Nan Cho
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hye-Mi Jin
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Young-Goun Jo
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hong-Joon Shin
- Department of Pulmonology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Bo Gun Kho
- Department of Pulmonology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Seung-Jung Kee
- Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Yong-Wook Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
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Shera S, Katzka W, Yang JC, Chang C, Arias-Jayo N, Lagishetty V, Balioukova A, Chen Y, Dutson E, Li Z, Mayer EA, Pisegna JR, Sanmiguel C, Pawar S, Zhang D, Leitman M, Hernandez L, Jacobs JP, Dong TS. Bariatric-induced microbiome changes alter MASLD development in association with changes in the innate immune system. Front Microbiol 2024; 15:1407555. [PMID: 39184030 PMCID: PMC11342267 DOI: 10.3389/fmicb.2024.1407555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
INTRODUCTION Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly 25% of the population and is the leading cause for liver-related mortality. Bariatric surgery is a well-known treatment for MASLD and obesity. Understanding the fundamental mechanisms by which bariatric surgery can alter MASLD can lead to new avenues of therapy and research. Previous studies have identified the microbiome's role in bariatric surgery and in inflammatory immune cell populations. The host innate immune system modulates hepatic inflammation and fibrosis, and thus the progression of MASLD. The precise role of immune cell types in the pathogenesis of MASLD remains an active area of investigation. The aim of this study was to understand the interplay between microbiota composition post-bariatric surgery and the immune system in MASLD. METHODS Eighteen morbidly obese females undergoing sleeve gastrectomy were followed pre-and post-surgery. Stool from four patients, showing resolved MASLD post-surgery with sustained weight loss, was transplanted into antibiotic treated mice. Mice received pre-or post-surgery stool and were fed a standard or high-fat diet. Bodyweight, food intake, and physiological parameters were tracked weekly. Metabolic parameters were measured post-study termination. RESULTS The human study revealed that bariatric surgery led to significant weight loss (p > 0.05), decreased inflammatory markers, and improved glucose levels six months post-surgery. Patients with weight loss of 20% or more showed distinct changes in blood metabolites and gut microbiome composition, notably an increase in Bacteroides. The mouse model confirmed surgery-induced microbiome changes to be a major factor in the reduction of markers and attenuation of MASLD progression. Mice receiving post-surgery fecal transplants had significantly less weight gain and liver steatosis compared to pre-surgery recipients. There was also a significant decrease in inflammatory cytokines interferon gamma, interleukin 2, interleukin 15, and mig. This was accompanied by alterations in liver immunophenotype, including an increase in natural killer T cells and reduction of Kupfer cells in the post-surgery transplant group. DISCUSSION Our findings suggest surgery induced microbial changes significantly reduce inflammatory markers and fatty liver progression. The results indicate a potential causal link between the microbiome and the host immune system, possibly mediated through modulation of liver NKT and Kupffer cells.
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Affiliation(s)
- Simer Shera
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - William Katzka
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Julianne C. Yang
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Candace Chang
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Nerea Arias-Jayo
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Venu Lagishetty
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Anna Balioukova
- Department of Surgery, UCLA Center for Obesity and METabolic Health (COMET), Los Angeles, CA, United States
- David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Yijun Chen
- Department of Surgery, UCLA Center for Obesity and METabolic Health (COMET), Los Angeles, CA, United States
- David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Erik Dutson
- Department of Surgery, UCLA Center for Obesity and METabolic Health (COMET), Los Angeles, CA, United States
- David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Zhaoping Li
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- UCLA Center for Human Nutrition, University of California, Los Angeles, Los Angeles, CA, United States
| | - Emeran A. Mayer
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, United States
| | - Joseph R. Pisegna
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Claudia Sanmiguel
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, United States
| | - Shrey Pawar
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - David Zhang
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Madelaine Leitman
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Laura Hernandez
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Jonathan P. Jacobs
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, United States
| | - Tien S. Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, United States
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Iba M, Kwon S, Kim C, Szabo M, Horan-Portelance L, Lopez-Ocasio M, Dagur P, Overk C, Rissman RA, Masliah E. Immunotherapy with an antibody against CD1d modulates neuroinflammation in an α-synuclein transgenic model of Lewy body like disease. J Neuroinflammation 2024; 21:93. [PMID: 38622654 PMCID: PMC11017481 DOI: 10.1186/s12974-024-03087-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/01/2024] [Indexed: 04/17/2024] Open
Abstract
The neuroinflammatory process in synucleinopathies of the aging population such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) involves microglial activation as well as infiltration of the CNS by T cells and natural killer T cells (NKTs). To evaluate the potential of targeting NKT cells to modulate neuroinflammation, we treated α-syn transgenic (tg) mice (e.g.: Thy1 promoter line 61) with an antibody against CD1d, which is a glycoprotein expressed in antigen presenting cells (APCs). CD1d-presented lipid antigens activate NKT cells through the interaction with T cell receptor in NKTs, resulting in the production of cytokines. Thus, we hypothesized that blocking the APC-NKT interaction with an anti-CD1d antibody might reduce neuroinflammation and neurodegeneration in models of DLB/PD. Treatment with the anti-CD1d antibody did not have effects on CD3 (T cells), slightly decreased CD4 and increased CD8 lymphocytes in the mice. Moreover, double labeling studies showed that compared to control (IgG) treated α-syn tg mice, treatment with anti-CD1d decreased numbers of CD3/interferon γ (IFN γ)-positive cells, consistent with NKTs. Further double labeling studies showed that CD1d-positive cells co-localized with the astrocytes marker GFAP and that anti-CD1d antibody reduced this effect. While in control α-syn tg mice CD3 positive cells were near astrocytes, this was modified by the treatment with the CD1d antibody. By qPCR, levels of IFN γ, CCL4, and interleukin-6 were increased in the IgG treated α-syn tg mice. Treatment with CD1d antibody blunted this cytokine response that was associated with reduced astrocytosis and microgliosis in the CNS of the α-syn tg mice treated with CD1d antibody. Flow cytometric analysis of immune cells in α-syn tg mice revealed that CD1d-tet + T cells were also increased in the spleen of α-syn tg mice, which treatment with the CD1d antibody reduced. Reduced neuroinflammation in the anti-CD1d-treated α-syn tg mice was associated with amelioration of neurodegenerative pathology. These results suggest that reducing infiltration of NKT cells with an antibody against CD1d might be a potential therapeutical approach for DLB/PD.
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Affiliation(s)
- Michiyo Iba
- Laboratory of Neurogenetics, Molecular Neuropathology Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Somin Kwon
- Laboratory of Neurogenetics, Molecular Neuropathology Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Changyoun Kim
- Laboratory of Neurogenetics, Molecular Neuropathology Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Marcell Szabo
- Laboratory of Neurogenetics, Molecular Neuropathology Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Liam Horan-Portelance
- Laboratory of Neurogenetics, Molecular Neuropathology Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Maria Lopez-Ocasio
- Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Pradeep Dagur
- Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Cassia Overk
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Robert A Rissman
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Eliezer Masliah
- Laboratory of Neurogenetics, Molecular Neuropathology Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
- Division of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20814, USA.
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Topchieva LV, Kurbatova IV, Dudanova OP, Vasileva AV, Zhulai GA. Immune cell balance as potential biomarker of progressing non-alcoholic fatty liver disease. GENES & CELLS 2024; 19:105-125. [DOI: 10.17816/gc610252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic, slowly progressive metabolic multifactorial disease. It is represented by several clinical and morphological forms: steatosis, nonalcoholic steatohepatitis (NASH) (with or without fibrosis), and liver cirrhosis. The search for minimally invasive and cost-effective biomarkers of NAFLD is a key task in the diagnosis, staging of progression, and long-term monitoring of NAFLD. This article discusses the possibility of using immune cell balance as potential minimally invasive peripheral markers of NAFLD progression. In the progression of NASH from steatosis to fibrosis and cirrhosis, inflammation plays an important role because of the activation of Kupffer cells and increased migration of monocytes, dendritic cells, neutrophils, and activated T lymphocytes into the tissues. Macrophages originating from monocytes, with NASH progression, gradually begin to prevail over the pool of resident macrophages. The risk of NASH and fibrosis development in patients with NAFLD increases with the ratio of neutrophils/lymphocytes in the liver. An increase in the Th17 cell count and a decrease in T-regulatory cell count can contribute to increased hepatic steatosis and inflammation development in NAFLD and accelerate the transition from simple steatosis to steatohepatitis and fibrosis. Information on the participation of noncoding RNAs in the regulation of the balance of immune cells in NAFLD is presented, which also allows us to consider them as additional, along with cellular, markers of disease progression.
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11
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Sun W, Qiu F, Zheng J, Fang L, Qu J, Zhang S, Jiang N, Zhou J, Zeng X, Zhou J. CD57-positive CD8 + T cells define the response to anti-programmed cell death protein-1 immunotherapy in patients with advanced non-small cell lung cancer. NPJ Precis Oncol 2024; 8:25. [PMID: 38297019 PMCID: PMC10830454 DOI: 10.1038/s41698-024-00513-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 12/08/2023] [Indexed: 02/02/2024] Open
Abstract
Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC). However, accurately identifying patients who will benefit from immunotherapy remains a challenge. This study aimed to discover potential biomarkers for predicting immunotherapy response in NSCLC patients. Single-cell mass cytometry (CyTOF) was utilized to analyze immune cell subsets in peripheral blood mononuclear cells (PBMCs) obtained from NSCLC patients before and 12 weeks after single-agent immunotherapy. The CyTOF findings were subsequently validated using flow cytometry and multiplex immunohistochemistry/immunofluorescence in PBMCs and tumor tissues, respectively. RNA sequencing (RNA-seq) was performed to elucidate the underlying mechanisms. In the CyTOF cohort (n = 20), a high frequency of CD57+CD8+ T cells in PBMCs was associated with durable clinical benefit from immunotherapy in NSCLC patients (p = 0.034). This association was further confirmed in an independent cohort using flow cytometry (n = 27; p < 0.001), with a determined cutoff value of 12.85%. The cutoff value was subsequently validated in another independent cohort (AUC = 0.733). We also confirmed the CyTOF findings in pre-treatment formalin-fixed and paraffin-embedded tissues (n = 90; p < 0.001). RNA-seq analysis revealed 475 differentially expressed genes (DEGs) between CD57+CD8+ T cells and CD57-CD8+ T cells, with functional analysis identifying DEGs significantly enriched in immune-related signaling pathways. This study highlights CD57+CD8+ T cells as a promising biomarker for predicting immunotherapy success in NSCLC patients.
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Affiliation(s)
- Wenjia Sun
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fengqi Qiu
- Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Jing Zheng
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liangjie Fang
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jingjing Qu
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shumeng Zhang
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Nan Jiang
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianying Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xun Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jianya Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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12
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Zhao W, Li M, Song S, Zhi Y, Huan C, Lv G. The role of natural killer T cells in liver transplantation. Front Cell Dev Biol 2024; 11:1274361. [PMID: 38250325 PMCID: PMC10796773 DOI: 10.3389/fcell.2023.1274361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Natural killer T cells (NKTs) are innate-like lymphocytes that are abundant in the liver and participate in liver immunity. NKT cells express both NK cell and T cell markers, modulate innate and adaptive immune responses. Type I and Type II NKT cells are classified according to the TCR usage, while they recognize lipid antigen in a non-classical major histocompatibility (MHC) molecule CD1d-restricted manner. Once activated, NKT cells can quickly produce cytokines and chemokines to negatively or positively regulate the immune responses, depending on the different NKT subsets. In liver transplantation (LTx), the immune reactions in a series of processes determine the recipients' long-term survival, including ischemia-reperfusion injury, alloresponse, and post-transplant infection. This review provides insight into the research on NKT cells subpopulations in LTx immunity during different processes, and discusses the shortcomings of the current research on NKT cells. Additionally, the CD56-expressing T cells are recognized as a NK-like T cell population, they were also discussed during these processes.
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Affiliation(s)
- Wenchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chen Huan
- Center of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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13
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Vavilova JD, Ustiuzhanina MO, Boyko AA, Streltsova MA, Kust SA, Kanevskiy LM, Iskhakov RN, Sapozhnikov AM, Gubernatorova EO, Drutskaya MS, Bychinin MV, Novikova ON, Sotnikova AG, Yusubalieva GM, Baklaushev VP, Kovalenko EI. Alterations in the CD56 - and CD56 + T Cell Subsets during COVID-19. Int J Mol Sci 2023; 24:9047. [PMID: 37240393 PMCID: PMC10219320 DOI: 10.3390/ijms24109047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/18/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied in COVID-19. This work aimed to analyze the activation and differentiation of both circulating NKT-like cells and CD56- T cells during COVID-19 among intensive care unit (ICU) patients, moderate severity (MS) patients, and convalescents. A decreased proportion of CD56+ T cells was found in ICU patients with fatal outcome. Severe COVID-19 was accompanied by a decrease in the proportion of CD8+ T cells, mainly due to the CD56- cell death, and a redistribution of the NKT-like cell subset composition with a predominance of more differentiated cytotoxic CD8+ T cells. The differentiation process was accompanied by an increase in the proportions of KIR2DL2/3+ and NKp30+ cells in the CD56+ T cell subset of COVID-19 patients and convalescents. Decreased percentages of NKG2D+ and NKG2A+ cells and increased PD-1 and HLA-DR expression levels were found in both CD56- and CD56+ T cells, and can be considered as indicators of COVID-19 progression. In the CD56- T cell fraction, increased CD16 levels were observed in MS patients and in ICU patients with lethal outcome, suggesting a negative role for CD56-CD16+ T cells in COVID-19. Overall, our findings suggest an antiviral role of CD56+ T cells in COVID-19.
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Affiliation(s)
- Julia D. Vavilova
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Maria O. Ustiuzhanina
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
- Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
| | - Anna A. Boyko
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Maria A. Streltsova
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Sofya A. Kust
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Leonid M. Kanevskiy
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Rustam N. Iskhakov
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Alexander M. Sapozhnikov
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
| | - Ekaterina O. Gubernatorova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Marina S. Drutskaya
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Division of Immunobiology and Biomedicine, Sirius University of Science and Technology, Sirius, Krasnodarsky Krai, 354349 Sochi, Russia
| | - Mikhail V. Bychinin
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies FMBA of Russia, 115682 Moscow, Russia
| | - Oksana N. Novikova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies FMBA of Russia, 115682 Moscow, Russia
| | - Anna G. Sotnikova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies FMBA of Russia, 115682 Moscow, Russia
| | - Gaukhar M. Yusubalieva
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies FMBA of Russia, 115682 Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Vladimir P. Baklaushev
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies FMBA of Russia, 115682 Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Elena I. Kovalenko
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (J.D.V.); (S.A.K.); (A.M.S.)
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14
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Tippalagama R, Chihab LY, Kearns K, Lewis S, Panda S, Willemsen L, Burel JG, Lindestam Arlehamn CS. Antigen-specificity measurements are the key to understanding T cell responses. Front Immunol 2023; 14:1127470. [PMID: 37122719 PMCID: PMC10140422 DOI: 10.3389/fimmu.2023.1127470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/30/2023] [Indexed: 05/02/2023] Open
Abstract
Antigen-specific T cells play a central role in the adaptive immune response and come in a wide range of phenotypes. T cell receptors (TCRs) mediate the antigen-specificities found in T cells. Importantly, high-throughput TCR sequencing provides a fingerprint which allows tracking of specific T cells and their clonal expansion in response to particular antigens. As a result, many studies have leveraged TCR sequencing in an attempt to elucidate the role of antigen-specific T cells in various contexts. Here, we discuss the published approaches to studying antigen-specific T cells and their specific TCR repertoire. Further, we discuss how these methods have been applied to study the TCR repertoire in various diseases in order to characterize the antigen-specific T cells involved in the immune control of disease.
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15
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Harnessing Innate Immunity to Treat Mycobacterium tuberculosis Infections: Heat-Killed Caulobacter crescentus as a Novel Biotherapeutic. Cells 2023; 12:cells12040560. [PMID: 36831226 PMCID: PMC9954702 DOI: 10.3390/cells12040560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/29/2023] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious disease worldwide. Approximately a quarter of the world population harbors latent Mtb infection without pathological consequences. Exposure of immunocompetent healthy individuals with Mtb does not result in active disease in more than 90% individuals, suggesting a defining role of host immunity to prevent and/or clear early infection. However, innate immune stimulation strategies have been relatively underexplored for the treatment of tuberculosis. In this study, we used cell culture and mouse models to examine the role of a heat-killed form of a non-pathogenic microbe, Caulobacter crescentus (HKCC), in inducing innate immunity and limiting Mtb infection. We also examined the added benefits of a distinct chemo-immunotherapeutic strategy that incorporates concurrent treatments with low doses of a first-line drug isoniazid and HKCC. This therapeutic approach resulted in highly significant reductions in disseminated Mtb in the lungs, liver, and spleen of mice compared to either agent alone. Our studies demonstrate the potential of a novel innate immunotherapeutic strategy with or without antimycobacterial drugs in controlling Mtb infection in mice and open new avenues for the treatment of tuberculosis in humans.
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16
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Radandish M, Esmaeil N, Khorvash F, Andalib A. Diagnostic Value of Natural Killer Cells, CD56+ CD16+ Natural Killer Cells, NLRP3, and Lactate Dehydrogenase in Severe/Critical COVID-19: A Prospective Longitudinal Study According to the Severe/Critical COVID-19 Definitions. Viral Immunol 2022; 35:616-628. [PMID: 36099205 DOI: 10.1089/vim.2022.0060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Innate immunity, as the first line of defense of our immune system, plays a crucial role in defending against SARS-CoV-2 infection and also its immunopathogenesis. We aim to investigate the immune status of natural killer (NK) cells, natural killer T (NKT) cells, and NLRP3 gene expression in COVID-19 patient blood samples. The immunophenotype of NK cell subsets and NKT cells was detected by flow cytometry and the expression of NLRP3 gene assessed by reverse transcriptase real-time polymerase chain reaction in 44 COVID-19 patients and 20 healthy individuals. The percentage of most of NK cell subpopulation and NKT cells was significantly decreased in COVID-19 patients. The percentage of CD56dim CD16- NK cell subsets, and NLRP3 gene expression increased. The percentage of total NK cells, CD56+ CD16+ NK cells, and NLRP3 gene expression had acceptable sensitivity and specificity for assisting diagnosis of severe/critical COVID-19. O2 saturation% and lactate dehydrogenase levels showed valuable diagnostic value to identify critical cases. The declined NK and NKT cells in COVID-19 patients and enhanced NLRP3 gene expression were associated with disease severity. Total NK cells, CD56+ CD16+ NK cells, and NLRP3 gene expression might be used as meaningful indicators for assisting diagnosis of severe/critical COVID-19.
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Affiliation(s)
- Maedeh Radandish
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nafiseh Esmaeil
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farzin Khorvash
- Department of Infectious Diseases, Faculty of Medicine, Nosocomial Infections Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Andalib
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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17
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Single-cell analysis reveals differences among iNKT cells colonizing peripheral organs and identifies Klf2 as a key gene for iNKT emigration. Cell Discov 2022; 8:75. [PMID: 35915069 PMCID: PMC9343440 DOI: 10.1038/s41421-022-00432-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/02/2022] [Indexed: 11/25/2022] Open
Abstract
Invariant natural killer T cell (iNKT) subsets are differentially distributed in various immune organs. However, it remains unclear whether iNKT cells exhibit phenotypical and functional differences in different peripheral organs and how thymic iNKT cells emigrate to peripheral organs. Here, we used single-cell RNA-seq to map iNKT cells from peripheral organs. iNKT1 cells from liver, spleen, and lymph node appear to have distinct phenotypic profiles and functional capabilities. However, iNKT17 transcriptomes were comparable across peripheral organs. In addition, by integrating data with a thymic iNKT cell study, we uncovered a transient population of recent thymic emigrants, a cluster of peripheral iNKT cells with high expression of transcription factor Kruppel-like factor 2 (Klf2). Deletion of Klf2 led to a severe impairment of iNKT differentiation and migration. Our study revealed that iNKT subsets are uniquely distributed in peripheral organs with some inter-local tissue variation, especially for iNKT1 cell, and identified Klf2 as a rheostat for iNKT cell migration and differentiation.
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18
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Li Y, Sharma A, Maciaczyk J, Schmidt-Wolf IGH. Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside. Int J Mol Sci 2022; 23:ijms23031311. [PMID: 35163235 PMCID: PMC8835986 DOI: 10.3390/ijms23031311] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/15/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.
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Affiliation(s)
- Yutao Li
- Center for Integrated Oncology (CIO), Department of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany;
| | - Amit Sharma
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany; (A.S.); (J.M.)
| | - Jarek Maciaczyk
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany; (A.S.); (J.M.)
- Department of Surgical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Ingo G. H. Schmidt-Wolf
- Center for Integrated Oncology (CIO), Department of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany;
- Correspondence: ; Tel.: +49-228-2871-7050
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19
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Chen Y, Zheng X, Wu C. The Role of the Tumor Microenvironment and Treatment Strategies in Colorectal Cancer. Front Immunol 2021; 12:792691. [PMID: 34925375 PMCID: PMC8674693 DOI: 10.3389/fimmu.2021.792691] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/15/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) has the second highest mortality rate among all cancers worldwide. Surgery, chemotherapy, radiotherapy, molecular targeting and other treatment methods have significantly prolonged the survival of patients with CRC. Recently, the emergence of tumor immunotherapy represented by immune checkpoint inhibitors (ICIs) has brought new immunotherapy options for the treatment of advanced CRC. As the efficacy of ICIs is closely related to the tumor immune microenvironment (TME), it is necessary to clarify the relationship between the immune microenvironment of CRC and the efficacy of immunotherapy to ensure that the appropriate drugs are selected. We herein review the latest research progress in the immune microenvironment and strategies related to immunotherapy for CRC. We hope that this review helps in the selection of appropriate treatment strategies for CRC patients.
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Affiliation(s)
- Yaping Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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20
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Abstract
Unconventional T cells are a diverse and underappreciated group of relatively rare lymphocytes that are distinct from conventional CD4+ and CD8+ T cells, and that mainly recognize antigens in the absence of classical restriction through the major histocompatibility complex (MHC). These non-MHC-restricted T cells include mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, γδ T cells and other, often poorly defined, subsets. Depending on the physiological context, unconventional T cells may assume either protective or pathogenic roles in a range of inflammatory and autoimmune responses in the kidney. Accordingly, experimental models and clinical studies have revealed that certain unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic biomarkers. The responsiveness of human Vγ9Vδ2 T cells and MAIT cells to many microbial pathogens, for example, has implications for early diagnosis, risk stratification and targeted treatment of peritoneal dialysis-related peritonitis. The expansion of non-Vγ9Vδ2 γδ T cells during cytomegalovirus infection and their contribution to viral clearance suggest that these cells can be harnessed for immune monitoring and adoptive immunotherapy in kidney transplant recipients. In addition, populations of NKT, MAIT or γδ T cells are involved in the immunopathology of IgA nephropathy and in models of glomerulonephritis, ischaemia-reperfusion injury and kidney transplantation.
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21
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Jiang Y, Tao Z, Chen H, Xia S. Endoplasmic Reticulum Quality Control in Immune Cells. Front Cell Dev Biol 2021; 9:740653. [PMID: 34660599 PMCID: PMC8511527 DOI: 10.3389/fcell.2021.740653] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022] Open
Abstract
The endoplasmic reticulum quality control (ERQC) system, including endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy, presides over cellular protein secretion and maintains proteostasis in mammalian cells. As part of the immune system, a variety of proteins are synthesized and assembled correctly for the development, activation, and differentiation of immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived-suppressor cells (MDSCs), B lymphocytes, T lymphocytes, and natural killer (NK) cells. In this review, we emphasize the role of the ERQC in these immune cells, and also discuss how the imbalance of ER homeostasis affects the immune response, thereby suggesting new therapeutic targets for immunotherapy.
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Affiliation(s)
- Yalan Jiang
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zehua Tao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hua Chen
- Department of Colorectal Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Sheng Xia
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
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22
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Hypoxia and the Receptor for Advanced Glycation End Products (RAGE) Signaling in Cancer. Int J Mol Sci 2021; 22:ijms22158153. [PMID: 34360919 PMCID: PMC8348933 DOI: 10.3390/ijms22158153] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hypoxia is characterized by an inadequate supply of oxygen to tissues, and hypoxic regions are commonly found in solid tumors. The cellular response to hypoxic conditions is mediated through the activation of hypoxia-inducible factors (HIFs) that control the expression of a large number of target genes. Recent studies have shown that the receptor for advanced glycation end products (RAGE) participates in hypoxia-dependent cellular adaptation. We review recent evidence on the role of RAGE signaling in tumor biology under hypoxic conditions.
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23
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Czaja AJ. Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease. World J Gastroenterol 2021; 27:3705-3733. [PMID: 34321839 PMCID: PMC8291028 DOI: 10.3748/wjg.v27.i25.3705] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/22/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological properties, indicate their involvement in chronic liver disease, and encourage investigations that clarify their actions and therapeutic implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their pathological role has been deduced from their deficiencies during active liver disease, and future investigations must clarify this role, link it to outcome, and explore therapeutic interventions.
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Affiliation(s)
- Albert J Czaja
- Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
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24
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Gan J, Mao XR, Zheng SJ, Li JF. Invariant natural killer T cells: Not to be ignored in liver disease. J Dig Dis 2021; 22:136-142. [PMID: 33421264 DOI: 10.1111/1751-2980.12968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/14/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022]
Abstract
The liver is an important immune organ. Hepatocellular injury can be caused by many factors, which further leads to chronic liver diseases by activating the immune system. Multiple immune cells, such as T lymphocytes, B lymphocytes, natural killer cells (NKs), natural killer T cells (NKTs), and γδT cells, accumulate and participate in the immune regulation of the liver. NKTs are an indispensable component of immune cells in the liver, and invariant natural killer T cells (iNKTs) are the main subpopulation of NKTs. iNKTs activated by glycolipid antigen presented on CD1d secrete a series of cytokines and also act on other immune cells through cell-to-cell contact. Studies on the relationship between iNKTs and liver immunity have provided clues to uncover the pathogenesis of liver diseases and develop a promising strategy for the diagnosis and treatment of liver diseases.
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Affiliation(s)
- Jian Gan
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
| | - Xiao Rong Mao
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
| | - Su Jun Zheng
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jun Feng Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
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25
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Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity. J Immunol Res 2021; 2021:6633824. [PMID: 33506055 PMCID: PMC7808823 DOI: 10.1155/2021/6633824] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/16/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
Recently, cell-mediated immune response in malignant neoplasms has become the focus in immunotherapy against cancer. However, in leukemia, most studies on the cytotoxic potential of T cells have concentrated only on T cells that recognize peptide antigens (Ag) presented by polymorphic molecules of the major histocompatibility complex (MHC). This ignores the great potential of unconventional T cell populations, which include gamma-delta T cells (γδ), natural killer T cells (NKT), and mucosal-associated invariant T cells (MAIT). Collectively, these T cell populations can recognize lipid antigens, specially modified peptides and small molecule metabolites, in addition to having several other advantages, which can provide more effective applications in cancer immunotherapy. In recent years, these cell populations have been associated with a repertoire of anti- or protumor responses and play important roles in the dynamics of solid tumors and hematological malignancies, thus, encouraging the development of new investigations in the area. This review focuses on the current knowledge regarding the role of unconventional T cell populations in the antitumor immune response in leukemia and discusses why further studies on the immunotherapeutic potential of these cells are needed.
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26
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Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses. Front Immunol 2020; 11:940. [PMID: 32499786 PMCID: PMC7243284 DOI: 10.3389/fimmu.2020.00940] [Citation(s) in RCA: 488] [Impact Index Per Article: 97.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/22/2020] [Indexed: 12/20/2022] Open
Abstract
The success of cancer immunotherapy relies on the knowledge of the tumor microenvironment and the immune evasion mechanisms in which the tumor, stroma, and infiltrating immune cells function in a complex network. The potential barriers that profoundly challenge the overall clinical outcome of promising therapies need to be fully identified and counteracted. Although cancer immunotherapy has increasingly been applied, we are far from understanding how to utilize different strategies in the best way and how to combine therapeutic options to optimize clinical benefit. This review intends to give a contemporary and detailed overview of the different roles of immune cells, exosomes, and molecules acting in the tumor microenvironment and how they relate to immune activation and escape. Further, current and novel immunotherapeutic options will be discussed.
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Affiliation(s)
| | | | - Angelica Loskog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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27
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The Traditional Chinese Medicine Fufang Shatai Heji (STHJ) Enhances Immune Function in Cyclophosphamide-Treated Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:3849847. [PMID: 32063984 PMCID: PMC6998758 DOI: 10.1155/2020/3849847] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/06/2019] [Accepted: 12/09/2019] [Indexed: 12/21/2022]
Abstract
Fufang Shatai Heji (STHJ) is a mixture of traditional Chinese medicines, such as Radix Adenophorae, Radix Pseudostellariae, and Radix Astragali. STHJ is commonly used to treat diseases caused by low immune function, for example, Sjögren's syndrome (SS). The primary objective of this study was to assess the immunopotentiating effect of STHJ using an immunosuppressive mouse model receiving cyclophosphamide (CTX). Following CTX treatment, STHJ was administered by oral gavage for 30 consecutive days. The percentage of specific lymphocyte subpopulations in the spleen was measured by flow cytometry. Levels of inflammatory factors in serum were detected by enzyme-linked immunosorbent assays (ELISAs). The administration of STHJ significantly elevated thymus and spleen indices, increased B cell and natural killer (NK) cell activities, and decreased CD8+ T, CD8+CD122+ T, NKT, and γδT cell activities in the CTX-treated mice. In addition, STHJ upregulated the expression of interleukin- (IL-) 2, IL-6, and tumor necrosis factor-α (TNF-α) and downregulated IL-10 expression in CTX-treated mice. In conclusion, STHJ effectively remitted CTX-induced immunosuppression by modulating the balance of lymphocyte subsets and cytokines. Our results suggest STHJ treatment could be used as an effective therapeutic approach to improve immune function in patients with low immunity.
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28
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Almeida CF, Sundararaj S, Le Nours J, Praveena T, Cao B, Burugupalli S, Smith DGM, Patel O, Brigl M, Pellicci DG, Williams SJ, Uldrich AP, Godfrey DI, Rossjohn J. Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors. Nat Commun 2019; 10:5242. [PMID: 31748533 PMCID: PMC6868179 DOI: 10.1038/s41467-019-12941-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 10/11/2019] [Indexed: 12/20/2022] Open
Abstract
Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that diverse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens. Natural killer T (NKT) cells include type I that express semi-invariant T cell receptor (TCR), and type II that cover a broader repertoire. Here the authors describe the crystal structure of a type II NKT TCR complexed with CD1d/antigen to propose that type II NKT TCRs may adapt multiple CD1d docking modes to maximise antigen recognition efficacy.
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Affiliation(s)
- Catarina F Almeida
- Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, 3010, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Srinivasan Sundararaj
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Jérôme Le Nours
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia
| | - T Praveena
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia
| | - Benjamin Cao
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Satvika Burugupalli
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Dylan G M Smith
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Onisha Patel
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Manfred Brigl
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Daniel G Pellicci
- Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, 3010, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Spencer J Williams
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, 3010, Australia.,School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Adam P Uldrich
- Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, 3010, Australia. .,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, 3010, Australia.
| | - Dale I Godfrey
- Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, 3010, Australia. .,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, 3010, Australia.
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. .,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia. .,Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
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29
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Pan H, Zhang G, Nie H, Li S, He S, Yang J. Sulfatide-activated type II NKT cells suppress immunogenic maturation of lung dendritic cells in murine models of asthma. Am J Physiol Lung Cell Mol Physiol 2019; 317:L578-L590. [PMID: 31432714 DOI: 10.1152/ajplung.00256.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Our previous study showed that sulfatide-activated type II natural killer T (NKT) cells can prevent allergic airway inflammation in an ovalbumin (OVA)-induced murine model of asthma, but the underlying mechanism is unclear. Recently, sulfatide-activated type II NKT cells were shown to modulate the function of dendritic cells in experimental autoimmune encephalomyelitis and nonobese diabetic mice. Thus, it was hypothesized that sulfatide-activated type II NKT cells may modulate the function of lung dendritic cells (LDCs) in asthmatic mice. Our data showed that, in our mouse models, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells resulted in reduced expression of surface maturation markers and proinflammatory cytokine production of LDCs. LDCs from sulfatide-treated asthmatic mice, in contrast to LDCs from PBS-treated asthmatic mice, significantly reduced allergic airway inflammation in vivo. However, we found no influence of sulfatide-activated type II NKT cells on the phenotypic and functional maturation of bone marrow-derived dendritic cells in vitro. In addition, adoptive transfer of sulfatide-activated type II NKT cells did not influence the phenotypic and functional maturation of LDCs in CD1d-/- mice, which lack both type I and II NKT cells, immunized and challenged with OVA. Our data reveal that sulfatide-activated type II NKT cells can suppress immunogenic maturation of LDCs to reduce allergic airway inflammation in mouse models of asthma, and it is possible that the immunomodulatory effect needs type I NKT cells.
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Affiliation(s)
- Huaqin Pan
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Guqin Zhang
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hanxiang Nie
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shuhua Li
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shaojun He
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiong Yang
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
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30
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Activated CD8+ T Cells Cause Long-Term Neurological Impairment after Traumatic Brain Injury in Mice. Cell Rep 2019; 29:1178-1191.e6. [DOI: 10.1016/j.celrep.2019.09.046] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 08/08/2019] [Accepted: 09/16/2019] [Indexed: 12/28/2022] Open
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31
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Tiwary S, Berzofsky JA, Terabe M. Altered Lipid Tumor Environment and Its Potential Effects on NKT Cell Function in Tumor Immunity. Front Immunol 2019; 10:2187. [PMID: 31620124 PMCID: PMC6759687 DOI: 10.3389/fimmu.2019.02187] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 08/30/2019] [Indexed: 01/26/2023] Open
Abstract
Natural killer T (NKT) cells are CD1d restricted T cells that mostly recognize lipid antigens. These cells share characteristics with both adaptive and innate immune cells and have multiple immunoregulatory roles. In a manner similar to innate immune cells, they respond quickly to stimuli and secrete large amounts of cytokines, amplifying and modulating the immune response. As T cells, they express T cell receptors (TCRs) and respond in an antigen-specific manner like conventional T cells. There are at least two subtypes of NKT cells, type I and type II, that differ in the nature of their TCR, either semi-invariant (type I) or diverse (type II). The two sub-types generally have opposing functions in tumor immunity, with type I promoting and type II suppressing tumor immunity, and they cross-regulate each other, forming an immunoregulatory axis. The tumor has multiple mechanisms by which it can evade immune-surveillance. One such mechanism involves alteration in tumor lipid repertoire and accumulation of lipids and fatty acids that favor tumor growth and evade anti-tumor immunity. Since NKT cells mostly recognize lipid antigens, an altered tumor lipid metabolic profile will also alter the repertoire of lipid antigens that can potentially affect their immune-modulatory function. In this review, we will explore the effects of alterations in the lipid metabolites on tumor growth, antigen cross-presentation, and overall effect on anti-tumor immunity, especially in the context of NKT cells.
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Affiliation(s)
- Shweta Tiwary
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Jay A. Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Masaki Terabe
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
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32
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Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade. PLoS One 2019; 14:e0221301. [PMID: 31419253 PMCID: PMC6697319 DOI: 10.1371/journal.pone.0221301] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 08/03/2019] [Indexed: 01/19/2023] Open
Abstract
Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.
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33
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Wang Y, Zhang C. The Roles of Liver-Resident Lymphocytes in Liver Diseases. Front Immunol 2019; 10:1582. [PMID: 31379818 PMCID: PMC6648801 DOI: 10.3389/fimmu.2019.01582] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/25/2019] [Indexed: 12/18/2022] Open
Abstract
Tissue-resident lymphocytes usually reside in barrier sites and are involved in innate and adaptive immunity. In recent years, many studies have shown that multiple types of lymphocytes are resident in the liver, including memory CD8+ T (TRM) cells; "unconventional" T cells, such as invariant natural killer T (iNKT) cells, mucosal associated invariant T (MAIT) cells, and γδT cells; innate lymphoid cells (ILCs) such as natural killer (NK) cells and other ILCs. Although diverse types of tissue-resident lymphocytes share similar phenotypes, functional properties, and transcriptional regulation, the unique microenvironment of the liver can reshape their phenotypic and functional characteristics. Liver-resident lymphocytes serve as sentinels and perform immunosurveillance in response to infection and non-infectious insults, and are involved in the maintenance of liver homeostasis. Under the pathological conditions, distinct liver-resident lymphocytes exert protective or pathological effects in the process of various liver diseases. In this review, we highlight the unique properties of liver-resident lymphocytes, and discuss their functional characteristics in different liver diseases.
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Affiliation(s)
- Yanan Wang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Cai Zhang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
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34
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Van Kaer L, Postoak JL, Wang C, Yang G, Wu L. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell Mol Immunol 2019; 16:531-539. [PMID: 30874627 PMCID: PMC6804597 DOI: 10.1038/s41423-019-0221-5] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/22/2019] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons. A hallmark of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), is autoimmunity against proteins of the myelin sheath. Most studies in this field have focused on the roles of CD4+ T lymphocytes, which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis. Consequently, the treatments for MS often target the inflammatory CD4+ T-cell responses. However, many other lymphocyte subsets contribute to the pathophysiology of MS and EAE, and these subsets include CD8+ T cells and B cells of the adaptive immune system, lymphocytes of the innate immune system such as natural killer cells, and subsets of innate-like T and B lymphocytes such as γδ T cells, natural killer T cells, and mucosal-associated invariant T cells. Several of these lymphocyte subsets can act as mediators of CNS inflammation, whereas others exhibit immunoregulatory functions in disease. Importantly, the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4+ T cells. Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE, with an emphasis on lymphocytes other than CD4+ T cells. A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.
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Affiliation(s)
- Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
| | - Joshua L Postoak
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Chuan Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Guan Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Lan Wu
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
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35
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Sebode M, Wigger J, Filpe P, Fischer L, Weidemann S, Krech T, Weiler-Normann C, Peiseler M, Hartl J, Tolosa E, Herkel J, Schramm C, Lohse AW, Arrenberg P. Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis. Front Immunol 2019; 10:1065. [PMID: 31191516 PMCID: PMC6546815 DOI: 10.3389/fimmu.2019.01065] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 04/25/2019] [Indexed: 01/06/2023] Open
Abstract
Background: Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH). Methods: NKT cells were analyzed by flow cytometry in peripheral blood and liver of AIH patients and control groups. α-galactosylceramide-loaded or sulfatide-loaded tetramers were used to detect type I or II NKT cells, respectively. Hepatic CD1d was stained by in situ-hybridization of liver biopsies. Results and Conclusions: Type II NKT cells were more prevalent in human peripheral blood and liver than type I NKT cells. In AIH patients, the frequency of sulfatide-reactive type II NKT cells was significantly increased in peripheral blood (0.11% of peripheral blood leukocytes) and liver (3.78% of intrahepatic leukocytes) compared to healthy individuals (0.05% and 1.82%) and patients with drug-induced liver injury (0.06% and 2.03%; p < 0.05). Intrahepatic type II NKT cells of AIH patients had a different cytokine profile than healthy subjects with an increased frequency of TNFα (77.8% vs. 59.1%, p < 0.05), decreased IFNγ (32.7% vs. 63.0%, p < 0.05) and a complete lack of IL-4 expressing cells (0% vs. 2.1%, p < 0.05). T cells in portal tracts expressed significantly more CD1d-RNA in AIH livers compared to controls. This study supports that in contrast to their assumed protective role in mice, human intrahepatic, sulfatide-reactive type II NKT cells displayed a proinflammatory cytokine profile in patients with AIH. Infiltrating T cells in portal areas of AIH patients overexpressed CD1d and could thereby activate type II NKT cells.
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Affiliation(s)
- Marcial Sebode
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Jennifer Wigger
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pamela Filpe
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lutz Fischer
- Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.,Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Moritz Peiseler
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Johannes Hartl
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Eva Tolosa
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Herkel
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.,Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Philomena Arrenberg
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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36
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Wei X, Qian J, Yao W, Chen L, Guan H, Chen Y, Xie Y, Lu H, Zhang Z, Shi L, Lin X. Hyperactivated peripheral invariant natural killer T cells correlate with the progression of HBV-relative liver cirrhosis. Scand J Immunol 2019; 90:e12775. [PMID: 31069827 DOI: 10.1111/sji.12775] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 04/06/2019] [Accepted: 04/30/2019] [Indexed: 12/21/2022]
Abstract
Invariant NKT (iNKT) cells express markers of both T and NK cells and may produce various cytokines to regulate liver immunity. However, the role of iNKT cells in the progression of HBV-relative liver cirrhosis (HBV-LC) is incompletely understood. Here, we investigated the impact of peripheral iNKT cells on a cohort of patients with HBV-LC. The frequency, number, activation status, apoptosis and proliferation ability of peripheral iNKT cells were detected with flow cytometry. The impact of peripheral iNKT cells on the proliferation of hepatocyte cell line (MIHA) and activation of hepatic stellate cell line (LX-2) was detected with flow cytometry and PCR. In HBV-LC patients, the frequency and absolute number of peripheral iNKT cells significantly reduced, but the expression levels of CD25, interleukin (IL)-4, IL-13 and interferon (IFN)-γ increased. No difference was observed in the proliferation and apoptosis of circulating iNKT cells between patients and healthy controls (HCs). CXCR6 (CD186), known to be closely associated with iNKT cells migration from the periphery to the liver, was highly expressed on peripheral iNKT cells in HBV-LC patients. Furthermore, peripheral iNKT cells had a profound impact on MIHA cell proliferation and LX-2 cell activation through IL-4 or IL-13. Our data suggest that in HBV-LC patients, highly activated peripheral iNKT cells may migrate to the liver and affect hepatocyte cell line (MIHA) proliferation and hepatic stellate cell line (LX-2) activation through the expression of type 2 cytokines, which may result in excessive healing and contributing to the progression of fibrosis toward cirrhosis in liver.
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Affiliation(s)
- Xin Wei
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jingjing Qian
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Weifeng Yao
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liling Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huaqin Guan
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yingxiao Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yaosheng Xie
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hong Lu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhuo Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Shi
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Lin
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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37
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IL-17 production by NKG2D-expressing CD56+ T cells in type 2 diabetes. Mol Immunol 2018; 106:22-28. [PMID: 30576948 DOI: 10.1016/j.molimm.2018.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 11/20/2018] [Accepted: 12/09/2018] [Indexed: 02/06/2023]
Abstract
T cells expressing CD56 (identified as CD3+CD56+) play a potential role in activation or regulation of other immune cells by secreting various cytokines. We hypothesized that these cells expressing the natural group 2, member D (NKG2D) could produce high levels of interleukin (IL)-17 in type 2 diabetes (T2D). CD56 + T cells expressing NKG2D of T2D patients, particularly in poor glycemic control (PC) predominantly produced higher IL-17 compared to the NKG2D negative population. IL-17 production of CD56 + T cells with NKG2D + was positively correlated with the level of HbA1c (N = 22, R2 = 0.120 and P = 0.044). Interestingly, CD56+ T cells with NKG2DHi of T2D patients had significantly higher IL-17 production than those of CD56 + T cells with NKG2DLow (P = 0.027) and showed statistically significant with P-value < 0.001 compared to CD56 + T cells with NKG2DHi of non-diabetic individuals (ND). In summary, CD56 + T cells expressing NKG2D, especially in the NKG2DHi population may be involved in pathogenesis and severity of T2D via IL-17.
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38
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Wanjalla CN, McDonnell WJ, Koethe JR. Adipose Tissue T Cells in HIV/SIV Infection. Front Immunol 2018; 9:2730. [PMID: 30559739 PMCID: PMC6286992 DOI: 10.3389/fimmu.2018.02730] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 11/05/2018] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue comprises one of the largest organs in the body and performs diverse functions including energy storage and release, regulation of appetite and other neuroendocrine signaling, and modulation of immuity, among others. Adipocytes reside in a complex compartment where antigen, antigen presenting cells, innate immune cells, and adaptive immune cells interact locally and exert systemic effects on inflammation, circulating immune cell profiles, and metabolic homeostasis. T lymphocytes are a major component of the adipose tissue milieu which are altered in disease states such as obesity and human immunodeficiency virus (HIV) infection. While obesity, HIV infection, and simian immunodeficiency virus (SIV; a non-human primate virus similar to HIV) infection are accompanied by enrichment of CD8+ T cells in the adipose tissue, major phenotypic differences in CD4+ T cells and other immune cell populations distinguish HIV/SIV infection from obesity. Furthermore, DNA and RNA species of HIV and SIV can be detected in the stromal vascular fraction of visceral and subcutaneous adipose tissue, and replication-competent HIV resides in local CD4+ T cells. Here, we review studies of adipose tissue CD4+ and CD8+ T cell populations in HIV and SIV, and contrast the findings with those reported in obesity.
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Affiliation(s)
- Celestine N Wanjalla
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Wyatt J McDonnell
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, United States.,Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - John R Koethe
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, United States
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39
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Wang SX, Yang CL, Zhang M, Zhang P, Liu RT, Zhang N, Yang B, Li XL, Dou YC, Duan RS. Sulfatides ameliorate experimental autoimmune neuritis by suppressing Th1/Th17 cells. J Neuroimmunol 2018; 326:55-61. [PMID: 30481614 DOI: 10.1016/j.jneuroim.2018.11.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/05/2018] [Accepted: 11/13/2018] [Indexed: 12/25/2022]
Abstract
Sulfatides have immunomodulatory functions, and play protective roles in multiple autoimmune diseases. In the present study, we showed that sulfatides ameliorated experimental autoimmune neuritis in Lewis rats induced with bovine peripheral myelin, which was associated with decreased proportions of Th1 and Th17 cells. Furthermore, compared control group, cells from sulfatide-treated rats exhibited lower potential in proliferation and IL-17 secretion in the presence of BPM or ConA in vitro. Moreover, sulfatides also reduced the proportions of NK and NKT cells. In summary, our study indicated that sulfatides might become a new therapeutic agent in Guillain-Barré syndrome in the future.
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Affiliation(s)
- Shu-Xia Wang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China; Department of Neurology, The Second People's Hospital of Liaocheng, Linqing, Shandong 252600, PR China
| | - Chun-Lin Yang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Min Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Peng Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Ru-Tao Liu
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Na Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Bing Yang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Xiao-Li Li
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Ying-Chun Dou
- College of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China
| | - Rui-Sheng Duan
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China.
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40
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Plavsic I, Žitinić I, Mikolasevic I, Poropat G, Hauser G. Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities? World J Gastrointest Endosc 2018; 10:259-266. [PMID: 30364685 PMCID: PMC6198307 DOI: 10.4253/wjge.v10.i10.259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/10/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Žitinić
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Ivana Mikolasevic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of health Studies, University of Rijeka, Rijeka 51000, Croatia
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41
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Marrero I, Maricic I, Feldstein AE, Loomba R, Schnabl B, Rivera-Nieves J, Eckmann L, Kumar V. Complex Network of NKT Cell Subsets Controls Immune Homeostasis in Liver and Gut. Front Immunol 2018; 9:2082. [PMID: 30254647 PMCID: PMC6141878 DOI: 10.3389/fimmu.2018.02082] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/22/2018] [Indexed: 12/23/2022] Open
Abstract
The liver-gut immune axis is enriched in several innate immune cells, including innate-like unconventional and adaptive T cells that are thought to be involved in the maintenance of tolerance to gut-derived antigens and, at the same time, enable effective immunity against microbes. Two subsets of lipid-reactive CD1d-restricted natural killer T (NKT) cells, invariant NKT (iNKT) and type II NKT cells present in both mice and humans. NKT cells play an important role in regulation of inflammation in the liver and gut due to their innate-like properties of rapid secretion of a myriad of pro-inflammatory and anti-inflammatory cytokines and their ability to influence other innate cells as well as adaptive T and B cells. Notably, a bi-directional interactive network between NKT cells and gut commensal microbiota plays a crucial role in this process. Here, we briefly review recent studies related to the cross-regulation of both NKT cell subsets and how their interactions with other immune cells and parenchymal cells, including hepatocytes and enterocytes, control inflammatory diseases in the liver, such as alcoholic and non-alcoholic steatohepatitis, as well as inflammation in the gut. Overwhelming experimental data suggest that while iNKT cells are pathogenic, type II NKT cells are protective in the liver. Since CD1d-dependent pathways are highly conserved from mice to humans, a detailed cellular and molecular understanding of these immune regulatory pathways will have major implications for the development of novel therapeutics against inflammatory diseases of liver and gut.
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Affiliation(s)
- Idania Marrero
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Igor Maricic
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Bernd Schnabl
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Jesus Rivera-Nieves
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Lars Eckmann
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Vipin Kumar
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
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42
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Singh AK, Tripathi P, Cardell SL. Type II NKT Cells: An Elusive Population With Immunoregulatory Properties. Front Immunol 2018; 9:1969. [PMID: 30210505 PMCID: PMC6120993 DOI: 10.3389/fimmu.2018.01969] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/10/2018] [Indexed: 12/20/2022] Open
Abstract
Natural killer T (NKT) cells are unique unconventional T cells that are reactive to lipid antigens presented on the non-polymorphic major histocompatibility class (MHC) I-like molecule CD1d. They have characteristics of both innate and adaptive immune cells, and have potent immunoregulatory roles in tumor immunity, autoimmunity, and infectious diseases. Based on their T cell receptor (TCR) expression, NKT cells are divided into two subsets, type I NKT cells with an invariant TCRα-chain (Vα24 in humans, Vα14 in mice) and type II NKT cells with diverse TCRs. While type I NKT cells are well-studied, knowledge about type II NKT cells is still limited, and it is to date only possible to identify subsets of this population. However, recent advances have shown that both type I and type II NKT cells play important roles in many inflammatory situations, and can sometimes regulate the functions of each other. Type II NKT cells can be both protective and pathogenic. Here, we review current knowledge on type II NKT cells and their functions in different disease settings and how these cells can influence immunological outcomes.
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Affiliation(s)
- Avadhesh Kumar Singh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Prabhanshu Tripathi
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Susanna L Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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43
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Sainz V, Moura LI, Peres C, Matos AI, Viana AS, Wagner AM, Vela Ramirez JE, S. Barata T, Gaspar M, Brocchini S, Zloh M, Peppas NA, Satchi-Fainaro R, F. Florindo H. α-Galactosylceramide and peptide-based nano-vaccine synergistically induced a strong tumor suppressive effect in melanoma. Acta Biomater 2018; 76:193-207. [PMID: 29940370 DOI: 10.1016/j.actbio.2018.06.029] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/20/2018] [Accepted: 06/21/2018] [Indexed: 12/24/2022]
Abstract
α-Galactosylceramide (GalCer) is a glycolipid widely known as an activator of Natural killer T (NKT) cells, constituting a promising adjuvant against cancer, including melanoma. However, limited clinical outcomes have been obtained so far. This study evaluated the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II melanoma-associated peptide antigens and the Toll-Like Receptor (TLR) ligands CpG and monophosphoryl lipid A (MPLA), which we intended to maximize following their co-delivery by a nanoparticle (NP). This is expected to improve GalCer capture by dendritic cells (DCs) and subsequent presentation to NKT cells, simultaneously inducing an anti-tumor specific T-cell mediated immunity. The combination of GalCer with melanoma peptides and TLR ligands successfully restrained tumor growth. The tumor volume in these animals was 5-fold lower than the ones presented by mice immunized with NPs not containing GalCer. However, tumor growth was controlled at similar levels by GalCer entrapped or in its soluble form, when mixed with antigens and TLR ligands. Those two groups showed an improved infiltration of T lymphocytes into the tumor, but only GalCer-loaded nano-vaccine induced a prominent and enhanced infiltration of NKT and NK cells. In addition, splenocytes of these animals secreted levels of IFN-γ and IL-4 at least 1.5-fold and 2-fold higher, respectively, than those treated with the mixture of antigens and adjuvants in solution. Overall, the combined delivery of the NKT agonist with TLR ligands and melanoma antigens via this multivalent nano-vaccine displayed a synergistic anti-tumor immune-mediated efficacy in B16F10 melanoma mouse model. STATEMENT OF SIGNIFICANCE Combination of α-galactosylceramide (GalCer), a Natural Killer T (NKT) cell agonist, with melanoma-associated antigens presented by MHC class I (Melan-A:26) and MHC class II (gp100:44) molecules, and Toll-like Receptor (TLR) ligands (MPLA and CpG), within nanoparticle matrix induced a prominent anti-tumor immune response able to restrict melanoma growth. An enhanced infiltration of NKT and NK cells into tumor site was only achieved when the combination GalCer, antigens and TLR ligands were co-delivered by the nanovaccine.
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44
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The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator? Can J Gastroenterol Hepatol 2018; 2018:8197937. [PMID: 30046564 PMCID: PMC6038587 DOI: 10.1155/2018/8197937] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
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45
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Gupta N, Kumar R, Agrawal B. New Players in Immunity to Tuberculosis: The Host Microbiome, Lung Epithelium, and Innate Immune Cells. Front Immunol 2018; 9:709. [PMID: 29692778 PMCID: PMC5902499 DOI: 10.3389/fimmu.2018.00709] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 03/22/2018] [Indexed: 12/31/2022] Open
Abstract
Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 million new infections and 1.8 million deaths every year globally. Efforts to control and eradicate TB are hampered by the rapid emergence of drug resistance and limited efficacy of the only available vaccine, BCG. Immunological events in the airways and lungs are of major importance in determining whether exposure to Mycobacterium tuberculosis (Mtb) results in successful infection or protective immunity. Several studies have demonstrated that the host microbiota is in constant contact with the immune system, and thus continually directs the nature of immune responses occurring during new infections. However, little is known about its role in the eventual outcome of the mycobacterial infection. In this review, we highlight the changes in microbial composition in the respiratory tract and gut that have been linked to the alteration of immune responses, and to the risk, prevention, and treatment of TB. In addition, we summarize our current understanding of alveolar epithelial cells and the innate immune system, and their interaction with Mtb during early infection. Extensive studies are warranted to fully understand the all-inclusive role of the lung microbiota, its interaction with epithelium and innate immune responses and resulting adaptive immune responses, and in the pathogenesis and/or protection from Mtb infection. Novel interventions aimed at influencing the microbiota, the alveolar immune system and innate immunity will shape future strategies of prevention and treatment for TB.
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Affiliation(s)
- Nancy Gupta
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Rakesh Kumar
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Babita Agrawal
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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46
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Jiang J, Wang GZ, Wang Y, Huang HZ, Li WT, Qu XD. Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res 2018; 367:81-88. [PMID: 29571949 DOI: 10.1016/j.yexcr.2018.03.025] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/19/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
Abstract
Hypoxia is associated with the progression of hepatocellular carcinoma through promotion of spontaneous metastasis but the mechanism remains unclear. Here, we hypothesis that tumor cell-derived HMGB1 orchestrates macrophages infiltration and promotes metastasis of HCC via enhancing macrophage-secreted IL-6 under hypoxia. HMGB1 expression was robustly exacerbated in tumors of HCC patients with PVTT. Meanwhile, hypoxia exposure gave rise to HMGB1 expression in hepatoma cells of human and mouse in a HIF-1α-dependent manner and subsequently induced the infiltration and reprogramming of macrophages to augment the expression of Il-6. Further study demonstrated macrophage-derived IL-6 enhanced the invasiveness and metastasis of murine HCC cells. Therefore, our study provides a novel understanding of the relationship between tumor cells and tumor associated macrophages (TAMs) in the context of hypoxia.
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Affiliation(s)
- Jiang Jiang
- Shanghai Institute of Medical Imaging, Shanghai, China; Department of Interventional Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guang-Zhi Wang
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ying Wang
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hao-Zhe Huang
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wen-Tao Li
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai, China.
| | - Xu-Dong Qu
- Shanghai Institute of Medical Imaging, Shanghai, China; Department of Interventional Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
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47
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Schönrich G, Raftery MJ. CD1-Restricted T Cells During Persistent Virus Infections: "Sympathy for the Devil". Front Immunol 2018; 9:545. [PMID: 29616036 PMCID: PMC5868415 DOI: 10.3389/fimmu.2018.00545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/02/2018] [Indexed: 12/12/2022] Open
Abstract
Some of the clinically most important viruses persist in the human host after acute infection. In this situation, the host immune system and the viral pathogen attempt to establish an equilibrium. At best, overt disease is avoided. This attempt may fail, however, resulting in eventual loss of viral control or inadequate immune regulation. Consequently, direct virus-induced tissue damage or immunopathology may occur. The cluster of differentiation 1 (CD1) family of non-classical major histocompatibility complex class I molecules are known to present hydrophobic, primarily lipid antigens. There is ample evidence that both CD1-dependent and CD1-independent mechanisms activate CD1-restricted T cells during persistent virus infections. Sophisticated viral mechanisms subvert these immune responses and help the pathogens to avoid clearance from the host organism. CD1-restricted T cells are not only crucial for the antiviral host defense but may also contribute to tissue damage. This review highlights the two edged role of CD1-restricted T cells in persistent virus infections and summarizes the viral immune evasion mechanisms that target these fascinating immune cells.
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Affiliation(s)
- Günther Schönrich
- Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Martin J Raftery
- Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
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48
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Krijgsman D, Hokland M, Kuppen PJK. The Role of Natural Killer T Cells in Cancer-A Phenotypical and Functional Approach. Front Immunol 2018. [PMID: 29535734 PMCID: PMC5835336 DOI: 10.3389/fimmu.2018.00367] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Natural killer T (NKT) cells are a subset of CD1d-restricted T cells at the interface between the innate and adaptive immune system. NKT cells can be subdivided into functional subsets that respond rapidly to a wide variety of glycolipids and stress-related proteins using T- or natural killer (NK) cell-like effector mechanisms. Because of their major modulating effects on immune responses via secretion of cytokines, NKT cells are also considered important players in tumor immunosurveillance. During early tumor development, T helper (TH)1-like NKT cell subsets have the potential to rapidly stimulate tumor-specific T cells and effector NK cells that can eliminate tumor cells. In case of tumor progression, NKT cells may become overstimulated and anergic leading to deletion of a part of the NKT cell population in patients via activation-induced cell death. In addition, the remaining NKT cells become hyporesponsive, or switch to immunosuppressive TH2-/T regulatory-like NKT cell subsets, thereby facilitating tumor progression and immune escape. In this review, we discuss this important role of NKT cells in tumor development and we conclude that there should be three important focuses of future research in cancer patients in relation with NKT cells: (1) expansion of the NKT cell population, (2) prevention and breaking of NKT cell anergy, and (3) skewing of NKT cells toward TH1-like subsets with antitumor activity.
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Affiliation(s)
- Daniëlle Krijgsman
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands
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Torina A, Guggino G, La Manna MP, Sireci G. The Janus Face of NKT Cell Function in Autoimmunity and Infectious Diseases. Int J Mol Sci 2018; 19:ijms19020440. [PMID: 29389901 PMCID: PMC5855662 DOI: 10.3390/ijms19020440] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 01/22/2018] [Accepted: 01/26/2018] [Indexed: 12/19/2022] Open
Abstract
Natural killer T cells (NKT) are a subset of T lymphocytes bridging innate and adaptive immunity. These cells recognize self and microbial glycolipids bound to non-polymorphic and highly conserved CD1d molecules. Three NKT cell subsets, type I, II, and NKT-like expressing different antigen receptors (TCR) were described and TCR activation promotes intracellular events leading to specific functional activities. NKT can exhibit different functions depending on the secretion of soluble molecules and the interaction with other cell types. NKT cells act as regulatory cells in the defense against infections but, on the other hand, their effector functions can be involved in the pathogenesis of several inflammatory disorders due to their exposure to different microbial or self-antigens, respectively. A deep understanding of the biology and functions of type I, II, and NKT-like cells as well as their interplay with cell types acting in innate (neuthrophils, innate lymphoid cells, machrophages, and dendritic cells) and adaptive immunity (CD4⁺,CD8⁺, and double negative T cells) should be important to design potential immunotherapies for infectious and autoimmune diseases.
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Affiliation(s)
- Alessandra Torina
- Experimental Zooprophylactic Institute of Sicily, Via Marinuzzi 3, 90100 Palermo, Italy.
| | - Giuliana Guggino
- Biomedical Department of Internal and Specialized Medicine, Rheumatology Section, University of Palermo, Piazza delle Cliniche 2, 90100 Palermo, Italy.
| | - Marco Pio La Manna
- Department of Biopathology and Medical Biotechnology, Section of General Pathology, University of Palermo, Via del Vespro 129, 90100 Palermo, Italy.
- Central Laboratory Advanced Diagnostic and Biological Research, University Hospital, Via del Vespro 129, 90100 Palermo, Italy.
| | - Guido Sireci
- Department of Biopathology and Medical Biotechnology, Section of General Pathology, University of Palermo, Via del Vespro 129, 90100 Palermo, Italy.
- Central Laboratory Advanced Diagnostic and Biological Research, University Hospital, Via del Vespro 129, 90100 Palermo, Italy.
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Khan MA, Aljarbou AN, Aldebasi YH, Alorainy MS, Rahmani AH, Younus H, Khan A. Liposomal formulation of glycosphingolipids from Sphingomonas paucimobilis induces antitumour immunity in mice. J Drug Target 2018; 26:709-719. [PMID: 29307241 DOI: 10.1080/1061186x.2018.1424857] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Natural Killer T (NKT) cells play an important role in host's anti-tumour immune response. Glycosphingolipids (GSLs) isolated from Sphingomonas paucimobilis have the ability to stimulate NKT cells. In this study, the activity of free GSLs or GSLs-incorporated liposomes (glycosphingosomes) was investigated against dimethyl-α-benzanthracene (DMBA)-induced tumours in mice. The anti-tumour immunity of GSLs- or glycosphingosomes-loaded bone marrow-derived dendritic cells (BMDCs) was investigated in tumour-bearing mice. The Immunotherapeutic potential of co-administration of liposomal doxorubicin (Lip-Dox) and GSLs or glycosphingosomes was assessed by measuring cytokine levels and VEGF in the tumour tissues. Pretreatment with glycosphingosomes significantly delayed the frequency of tumour formation. Immunotherapy with glycosphingosomes-loaded BMDCs increased serum IFN-γ level and survival rate in mice. The effect of immunotherapy was dependent on effector functions of NK cells because the depletion of NK cells abolished the effects of immunotherapy. There was reduced tumour growth with low expression of VEGF in the group of mice treated with glycosphingosomes and Lip-Dox combination. Moreover, the splenocytes secreted higher levels of IFN-γ, IL-12 and lower TGF-β level. The results of this study indicate that glycosphingosomes can induce better antitumour immunity and may be considered a novel formulation in antitumour therapy.
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Affiliation(s)
- Masood A Khan
- a College of Applied Medical Sciences , Qassim University , Buraydah , Saudi Arabia
| | - Ahmed N Aljarbou
- b College of Pharmacy , Qassim University , Buraydah , Saudi Arabia
| | - Yousef H Aldebasi
- a College of Applied Medical Sciences , Qassim University , Buraydah , Saudi Arabia
| | | | - Arshad H Rahmani
- a College of Applied Medical Sciences , Qassim University , Buraydah , Saudi Arabia
| | - Hina Younus
- d Interdisciplinary Biotechnology Unit , Aligarh Muslim University , Aligarh , India
| | - Arif Khan
- a College of Applied Medical Sciences , Qassim University , Buraydah , Saudi Arabia
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