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Nilsson M, Kozyrev SV, Saellström S, Johansson S, Andersson G, Lindblad-Toh K, Hansson-Hamlin H, Rönnberg H. Elevated levels of IL-12/IL-23p40 in Nova Scotia Duck Tolling Retrievers with autoimmune disease and lymphoma. Sci Rep 2024; 14:11624. [PMID: 38773194 PMCID: PMC11109178 DOI: 10.1038/s41598-024-62265-y] [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: 07/03/2023] [Accepted: 05/15/2024] [Indexed: 05/23/2024] Open
Abstract
The Nova Scotia Duck Tolling Retriever (NSDTR) is predisposed to immune mediated rheumatic disease (IMRD), steroid-responsive meningitis-arteritis (SRMA) and certain forms of cancer. Cytokines are the main regulators of the immune system. Interleukin 2 is a cytokine involved in activation of T regulatory cells, playing a role in central tolerance and tumor immunity. Interleukin 12 and interleukin 23 share the same subunit, p40, and are both pro-inflammatory cytokines. The aim of this study was to compare levels of IL-2 in healthy NSDTRs to those with cancer or autoimmune disease and to compare levels of IL-12/IL-23p40 in healthy NSDTRs and beagles versus NSDTRs with cancer or autoimmune disease. 62 dogs were included in the analysis of IL-12/IL-23p40; healthy NSDTRs (n = 16), healthy beagles (n = 16), NSDTRs autoimmune (n = 18) and NDSTRs lymphoma/mastocytoma (n = 12) and 68 dogs for IL-2; healthy (n = 20), autoimmune (n = 36) and lymphoma/mastocytoma/adenocarcinoma (n = 12). NSDTRs with autoimmune disease had higher levels of IL-12/IL-23p40 compared to healthy dogs (p = 0.008). NSDTRs with lymphoma also had higher levels of IL-12/IL-23p40 compared to healthy NSDTRs (p = 0.002). There was no difference in levels of IL-2 between healthy and diseased NSDTR. Statistical analysis was performed using Bonferroni corrections for multiple testing. These findings can contribute to the knowledge of autoimmune disease and cancer in dogs.
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Affiliation(s)
- Malin Nilsson
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
| | - Sergey V Kozyrev
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Sara Saellström
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Siri Johansson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
- Anicura Kalmarsund Animal Hospital, Kalmar, Sweden
| | - Göran Andersson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Kerstin Lindblad-Toh
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- SciLifeLab, Uppsala University, Uppsala, Sweden
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Helene Hansson-Hamlin
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Henrik Rönnberg
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
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A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model. Int J Mol Sci 2022; 23:ijms23116059. [PMID: 35682738 PMCID: PMC9181410 DOI: 10.3390/ijms23116059] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 11/25/2022] Open
Abstract
In this study, the immunomodulatory effects of a sequential micro-immunotherapy medicine, referred as MIM-seq, were appraised in human primary M1 and M2 macrophages, in which the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-12, IL-23, and tumor necrosis factor (TNF)-alpha, was inhibited. In addition, the potential anti-proliferative effects of MIM-seq on tumor cells was assessed in three models of colorectal cancer (CRC): an in vitro two-dimensions (2D) model of HCT-116 cells, an in vitro tri-dimensional (3D) model of spheroids, and an in vivo model of subcutaneous xenografted mice. In these models, MIM-seq displayed anti-proliferative effects when compared with the vehicle. In vivo, the tumor growth was slightly reduced in MIM-seq-treated animals. Moreover, MIM-seq could slightly reduce the growth of our spheroid models, especially under serum-deprivation. When MIM-seq was combined with two well-known anti-cancerogenic agents, either resveratrol or etoposide, MIM-seq could even further reduce the spheroid’s volume, pointing up the need to further assess whether MIM-seq could be beneficial for CRC patients as an adjuvant therapy. Altogether, these data suggest that MIM-seq could have anti-tumor properties against CRC and an immunomodulatory effect towards the mediators of inflammation, whose systemic dysregulation is considered to be a poor prognosis for patients.
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Aubin AM, Lombard-Vadnais F, Collin R, Aliesky HA, McLachlan SM, Lesage S. The NOD Mouse Beyond Autoimmune Diabetes. Front Immunol 2022; 13:874769. [PMID: 35572553 PMCID: PMC9102607 DOI: 10.3389/fimmu.2022.874769] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/21/2022] [Indexed: 12/19/2022] Open
Abstract
Autoimmune diabetes arises spontaneously in Non-Obese Diabetic (NOD) mice, and the pathophysiology of this disease shares many similarities with human type 1 diabetes. Since its generation in 1980, the NOD mouse, derived from the Cataract Shinogi strain, has represented the gold standard of spontaneous disease models, allowing to investigate autoimmune diabetes disease progression and susceptibility traits, as well as to test a wide array of potential treatments and therapies. Beyond autoimmune diabetes, NOD mice also exhibit polyautoimmunity, presenting with a low incidence of autoimmune thyroiditis and Sjögren's syndrome. Genetic manipulation of the NOD strain has led to the generation of new mouse models facilitating the study of these and other autoimmune pathologies. For instance, following deletion of specific genes or via insertion of resistance alleles at genetic loci, NOD mice can become fully resistant to autoimmune diabetes; yet the newly generated diabetes-resistant NOD strains often show a high incidence of other autoimmune diseases. This suggests that the NOD genetic background is highly autoimmune-prone and that genetic manipulations can shift the autoimmune response from the pancreas to other organs. Overall, multiple NOD variant strains have become invaluable tools for understanding the pathophysiology of and for dissecting the genetic susceptibility of organ-specific autoimmune diseases. An interesting commonality to all autoimmune diseases developing in variant strains of the NOD mice is the presence of autoantibodies. This review will present the NOD mouse as a model for studying autoimmune diseases beyond autoimmune diabetes.
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Affiliation(s)
- Anne-Marie Aubin
- Immunology-Oncology Division, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada
| | - Félix Lombard-Vadnais
- Immunology-Oncology Division, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Roxanne Collin
- Immunology-Oncology Division, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada
- CellCarta, Montreal, QC, Canada
| | - Holly A. Aliesky
- Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Sandra M. McLachlan
- Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Sylvie Lesage
- Immunology-Oncology Division, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada
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Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, Li Z, Pan CX. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol 2021; 14:156. [PMID: 34579759 PMCID: PMC8475356 DOI: 10.1186/s13045-021-01164-5] [Citation(s) in RCA: 362] [Impact Index Per Article: 90.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022] Open
Abstract
Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.
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Affiliation(s)
- Shaoming Zhu
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,Department of Urology, Beijing Chao-Yang Hospital, Beijing, China
| | - Tian Zhang
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, DUMC 103861, Durham, NC, 27710, USA
| | - Lei Zheng
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Hongtao Liu
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,University of Chicago, Chicago, IL, USA
| | - Wenru Song
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,Kira Pharmaceuticals, Cambridge, MA, USA
| | - Delong Liu
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,New York Medical College, Valhalla, NY, USA
| | - Zihai Li
- Chinese American Hematologist and Oncologist Network, New York, NY, USA. .,Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA.
| | - Chong-Xian Pan
- Chinese American Hematologist and Oncologist Network, New York, NY, USA. .,Harvard Medical School, West Roxbury, MA, 02132, USA.
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Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis. Dig Dis Sci 2021; 66:2493-2512. [PMID: 32833154 DOI: 10.1007/s10620-020-06562-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/12/2020] [Indexed: 12/11/2022]
Abstract
Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8+ T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.
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Dehbashi M, Hojati Z, Motovali-bashi M, Ganjalikhany MR, Cho WC, Shimosaka A, Navabi P, Ganjalikhani-Hakemi M. A Novel CAR Expressing NK Cell Targeting CD25 With the Prospect of Overcoming Immune Escape Mechanism in Cancers. Front Oncol 2021; 11:649710. [PMID: 34055618 PMCID: PMC8160382 DOI: 10.3389/fonc.2021.649710] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023] Open
Abstract
For many years, high-affinity subunit of IL-2 receptor (CD25) has been considered as a promising therapeutic target for different pathologic conditions like allograft rejection, autoimmunity, and cancers. Although CD25 is transiently expressed by newly-activated T cells, it is the hallmark of regulatory T (Treg) cells which are the most important immunosuppressive elements in tumor microenvironment. Thus, Tregs can be considered as a potential target for chimeric antigen receptor (CAR)-based therapeutic approaches. On the other hand, due to some profound adverse effects pertaining to the use of CAR T cells, CAR NK cells have caught researchers' attention as a safer choice. Based on these, the aim of this study was to design and develop a CAR NK cell against CD25 as the most prominent biomarker of Tregs with the prospect of overcoming immune escape mechanism in solid and liquid cancers. In the current study, an anti-CD25 CAR was designed and evaluated by comprehensive in silico analyses. Then, using lentiviral transduction system, NK-92 cell line was engineered to express this anti-CD25 CAR construct. In vitro functional analyses of anti-CD25 CAR for its reactivity against CD25 antigen as well as for cytotoxicity and cytokine production assays against CD25 bearing Jurkat cell line were done. In silico analyses demonstrated that the anti-CD25 CAR transcript and scFv protein structures were stable and had proper interaction with the target. Also, in vitro analyses showed that the anti-CD25 CAR-engineered NK-92 cells were able to specifically detect and lyse target cells with an appropriate cytokine production and cytotoxic activity. To conclude, the results showed that this novel CAR NK cell is functional and warrant further investigations.
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Affiliation(s)
- Moein Dehbashi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Zohreh Hojati
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Majid Motovali-bashi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mohamad Reza Ganjalikhany
- Division of Biochemistry, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
| | - Akihiro Shimosaka
- Institute of Hematology, Peking Union Medical College, Beijing, China
| | - Parnian Navabi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mazdak Ganjalikhani-Hakemi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Wrage M, Kaltwasser J, Menge S, Mattner J. CD101 as an indicator molecule for pathological changes at the interface of host-microbiota interactions. Int J Med Microbiol 2021; 311:151497. [PMID: 33773220 DOI: 10.1016/j.ijmm.2021.151497] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/22/2021] [Accepted: 03/16/2021] [Indexed: 11/21/2022] Open
Abstract
Intestinal microbiota signal to local and distant tissues in the body. Thus, they also regulate biochemical, metabolic and immunological processes in the gut and in the pancreas. Vice versa, eating habits or the immune system of the host shape the intraluminal microbiota. Disruptions of these versatile host-microbiota interactions underlie the pathogenesis of complex immune-mediated disorders such as inflammatory bowel disease (IBD) or type 1 diabetes (T1D). Consequently, dysbiosis and increased intestinal permeability associated with both disorders change the biology of underlying tissues, as evidenced, for example, by an altered expression of surface markers such as CD101 on immune cells located at these dynamic host-microbiota interfaces. CD101, a heavily glycosylated member of the immunoglobulin superfamiliy, is predominantly detected on myeloid cells, intraepithelial lymphocytes (IELs) and regulatory T cells (Tregs) in the gut. The expression of CD101 on both myeloid cells and T lymphocytes protects from experimental enterocolitis and T1D. The improved outcome of both diseases is associated with an anti-inflammatory cytokine profile and a reduced expansion of T cells. However, distinct bacteria suppress the expression of CD101 on myeloid cells, similar as does inflammation on T cells. Thus, the reduced CD101 expression in T1D and IBD patients might be a consequence of an altered composition of the intestinal microbiota, enhanced bacterial translocation and a subsequent primining of local and systemic inflammatory immune responses.
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Affiliation(s)
- Marius Wrage
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Johanna Kaltwasser
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Sonja Menge
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany.
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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9
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Mullins GN, Valentine KM, Al-Kuhlani M, Davini D, Jensen KDC, Hoyer KK. T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice. Sci Rep 2020; 10:21994. [PMID: 33319815 PMCID: PMC7738527 DOI: 10.1038/s41598-020-78975-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 11/23/2020] [Indexed: 01/27/2023] Open
Abstract
IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically distinct autoimmune progression, with approximately a quarter dying by 21 days of age and half dying after 30 days. This research aims to define immune parameters and cytokine signaling that distinguish cohorts of IL-2Rα-KO mice that develop early- versus late-stage autoimmune disease. To investigate these differences, we evaluated complete blood counts (CBC), antibody binding of RBCs, T cell numbers and activation, hematopoietic progenitor changes, and signaling kinetics, during autoimmune hemolytic anemia (AIHA) and bone marrow failure. We identified several alterations that, when combined, correlate to disease kinetics. Early onset disease correlates with anti-RBC antibodies, lower hematocrit, and reduced IL-7 signaling. CD8 regulatory T cells (Tregs) have enhanced apoptosis in early disease. Further, early and late end stage disease, while largely similar, had several differences suggesting distinct mechanisms drive autoimmune disease kinetics. Therefore, IL-2Rα-KO disease pathology rates, driven by T cell signaling, promote effector T cell activation and expansion and Treg dysfunction.
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Affiliation(s)
- Genevieve N Mullins
- Quantitative and Systems Biology Graduate Program, University of California Merced, Merced, CA, 95343, USA
- Health Sciences Research Institute, University of California Merced, Merced, CA, 95343, USA
| | - Kristen M Valentine
- Quantitative and Systems Biology Graduate Program, University of California Merced, Merced, CA, 95343, USA
- Health Sciences Research Institute, University of California Merced, Merced, CA, 95343, USA
| | - Mufadhal Al-Kuhlani
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, Merced, CA, 95343, USA
| | - Dan Davini
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, Merced, CA, 95343, USA
| | - Kirk D C Jensen
- Quantitative and Systems Biology Graduate Program, University of California Merced, Merced, CA, 95343, USA
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, Merced, CA, 95343, USA
- Health Sciences Research Institute, University of California Merced, Merced, CA, 95343, USA
| | - Katrina K Hoyer
- Quantitative and Systems Biology Graduate Program, University of California Merced, Merced, CA, 95343, USA.
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, Merced, CA, 95343, USA.
- Health Sciences Research Institute, University of California Merced, Merced, CA, 95343, USA.
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Amarnath S, Brown ML. Harnessing proteases for T regulatory cell immunotherapy. Eur J Immunol 2020; 50:770-778. [PMID: 32383480 DOI: 10.1002/eji.201948270] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 03/08/2020] [Accepted: 05/06/2020] [Indexed: 12/27/2022]
Abstract
The immune system is tightly regulated by a subset of T cells defined as regulatory T cells (Tregs). Tregs maintain immune homeostasis by restraining unwarranted immune cell activation and effector function. Here, we discuss an important but underappreciated role of proteases in controlling Treg function. Proteases regulate a number of vital processes that determine T cell immune responses and some of them such as furin, ADAM (through regulating LAG receptor), MALT, and asparaginyl endopeptidase are implicated in Treg immunobiology. Targeted protease inhibition, using either small molecule inhibitors or gene deficient mice has demonstrated their specificity in modulating Treg function in experimental murine models. These data further highlight the ability of proteases to specifically regulate Tregs but no other T effector lineages. Taken together, it is apparent that incorporating proteases as targets within Treg cell engineering protocols may enable generation of robust Treg cellular therapeutics. These engineered Tregs may possess enhanced regulatory function along with resistance to lineage deviation in inflammatory disease such as colitis and graft versus host disease. Within this review, we summarize research on the role of proteases in regulating Treg function and discuss the translational potential of harnessing Treg function by targeting protease driven regulatory pathways.
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Affiliation(s)
- Shoba Amarnath
- NUTranslational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Marnie L Brown
- NUTranslational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
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Orozco Valencia A, Camargo Knirsch M, Suavinho Ferro E, Antonio Stephano M. Interleukin-2 as immunotherapeutic in the autoimmune diseases. Int Immunopharmacol 2020; 81:106296. [PMID: 32058934 DOI: 10.1016/j.intimp.2020.106296] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 02/04/2020] [Accepted: 02/05/2020] [Indexed: 12/27/2022]
Abstract
Interleukins, also called cytokines are secretory proteins that bind to specific receptors and play a critical role in the intercellular communication between cells of the immune system. Cytokines are mainly produced by T lymphocytes, macrophages and eosinophils. Among its functions are the activation and suppression of immune system responses, induction of cell division and regulation of memory cells. Interleukin 2 (IL-2) is a secretory monomeric glycoprotein composed of 149 amino acids containing a signal peptide of 20 amino acids. It is classified as a member of the type I cytokines family. IL-2 binds to its receptor (IL-2R receptor) with high affinity and its signaling function promotes the activation of various subtypes of lymphocytes during the process of cell differentiation to generate an immune or homeostatic response. The specificity of IL-2 depends on its binding to low, medium or high-affinity receptors. Interleukin 2 acts as a regulator of the proliferation of CD4+ and CD8+ T cells. There is a relationship between IL-2 and autoimmune diseases due to its influence in the differentiation of T helper cells, which in turn directly influence immunological response processes. Therefore, IL-2 is a key element in the control and treatment of those diseases. In recent years, many therapeutic agents based on biomolecules and recombinant chimeric proteins have been developed to treat different autoimmune diseases. In this review, we focus on the use of interleukin 2 as a versatile therapeutic agent, alone or associated with other molecules to increase the efficiency of autoimmune disease treatment.
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Affiliation(s)
- Alexy Orozco Valencia
- Department of Pharmaceutical Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
| | - Marcos Camargo Knirsch
- Department of Pharmaceutical Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
| | - Emer Suavinho Ferro
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marco Antonio Stephano
- Department of Pharmaceutical Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
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Abstract
Foxp3-expressing CD4+ regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.
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Affiliation(s)
- Peter A Savage
- Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA; , ,
| | - David E J Klawon
- Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA; , ,
| | - Christine H Miller
- Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA; , ,
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Cangemi M, Montico B, Faè DA, Steffan A, Dolcetti R. Dissecting the Multiplicity of Immune Effects of Immunosuppressive Drugs to Better Predict the Risk of de novo Malignancies in Solid Organ Transplant Patients. Front Oncol 2019; 9:160. [PMID: 30972289 PMCID: PMC6445870 DOI: 10.3389/fonc.2019.00160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 02/25/2019] [Indexed: 12/15/2022] Open
Abstract
De novo malignancies constitute an emerging cause of morbidity after solid organ transplant (SOT), significantly affecting the long-term survival of transplant recipients. Pharmacologic immunosuppression may functionally impair the immunosurveillance in these patients, thereby increasing the risk of cancer development. Nevertheless, the multiplicity and heterogeneity of the immune effects induced by immunosuppressive drugs limit the current possibilities to reliably predict the risk of de novo malignancy in SOT patients. Therefore, there is the pressing need to better characterize the immune dysfunctions induced by the different immunosuppressive regimens administered to prevent allograft rejection to tailor more precisely the therapeutic schedule and decrease the risk of de novo malignancies. We herein highlight the impact exerted by different classes of immunosuppressants on the most relevant immune cells, with a particular focus on the effects on dendritic cells (DCs), the main regulators of the balance between immunosurveillance and tolerance.
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Affiliation(s)
- Michela Cangemi
- Immunopathology and Cancer Biomarkers, Translational Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Barbara Montico
- Immunopathology and Cancer Biomarkers, Translational Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Damiana A Faè
- Immunopathology and Cancer Biomarkers, Translational Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Translational Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Riccardo Dolcetti
- Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD, Australia
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Hagihara Y, Yoshimatsu Y, Mikami Y, Takada Y, Mizuno S, Kanai T. Epigenetic regulation of T helper cells and intestinal pathogenicity. Semin Immunopathol 2019; 41:379-399. [PMID: 30891628 DOI: 10.1007/s00281-019-00732-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
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Abo H, Flannigan KL, Geem D, Ngo VL, Harusato A, Denning TL. Combined IL-2 Immunocomplex and Anti-IL-5 mAb Treatment Expands Foxp3 + Treg Cells in the Absence of Eosinophilia and Ameliorates Experimental Colitis. Front Immunol 2019; 10:459. [PMID: 30930900 PMCID: PMC6428029 DOI: 10.3389/fimmu.2019.00459] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 01/08/2023] Open
Abstract
Interleukin (IL)-2 is expressed during T cell activation and induces the proliferation and differentiation of T cells. CD4+Foxp3+ regulatory T cells (Tregs) constitutively express the high affinity IL-2 receptor (CD25/IL-2Rα) and rapidly respond to IL-2 to elaborate numerous suppressive mechanisms that limit immune-mediated pathologies. Accumulating evidence supports the concept that an aberrant balance between Tregs and Teff contribute to the pathology of intestinal inflammation and that the IL-2/Treg axis is a potential pathway to exploit for the treatment of inflammatory bowel disease (IBD). Here, we show that treatment of mice with IL-2/IL-2 antibody (JES6-1) immunocomplex during DSS-induced colitis induced Foxp3+ Treg expansion, but also potently stimulated GATA3+ type 2 innate lymphoid cell (ILC2) proliferation and high-level expression of IL-5. Furthermore, IL-2/JES6-1 treatment resulted in massive eosinophil accumulation and activation in the inflamed colon, and afforded only modest protection from colitis. In light of these findings, we observed that combined IL-2/JES6-1 and anti-IL-5 mAb treatment was most effective at ameliorating DSS-induced colitis compared to either treatment alone and that this regimen allowed for Foxp3+ Treg expansion without concomitant eosinophilia. Collectively, our findings provide insight into how blockade of IL-5 may aid in optimizing IL-2 immunotherapy for the treatment of intestinal inflammation.
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Affiliation(s)
- Hirohito Abo
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Kyle L Flannigan
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Duke Geem
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Vu L Ngo
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Akihito Harusato
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Timothy L Denning
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
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16
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da Silva JMC, Azevedo ADN, Barbosa RPDS, Teixeira MP, Vianna TAG, Fittipaldi J, Cabral VR, Paiva LSD. Ouabain Decreases Regulatory T Cell Number in Mice by Reducing IL-2 Secretion. Neuroimmunomodulation 2019; 26:188-197. [PMID: 31412342 DOI: 10.1159/000501720] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/24/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Ouabain (OUA) is a cardiotonic glycoside originally extracted from African plants. It has also been described as an endogenous component in mammals, being released in stress situations mainly by the adrenal gland. OUA has been reported to be capable of inhibiting mitogen-induced lymphocyte proliferation and also affects B and T lymphocytes. OBJECTIVES The aim of this work is to show the effects of OUA in peripheral T lymphocytes. METHODS In the in vivo experiments, mice were injected intraperitoneally for 3 consecutive days with RPMI medium (control group) or 0.56 mg/kg of OUA diluted in RPMI medium (OUA group). On the fourth day, spleen or mesenteric lymph nodes were removed. RESULTS OUA significantly reduced the number of CD4+ T lymphocytes in the spleen, especially regulatory T cells (Tregs). In vitro OUA did not inhibit the proliferation of CD4+T lymphocytes stimulated with anti-CD3 neither was able to induce the apoptosis of CD4+ nor Tregs. There was no increase in the number or percentage of T lymphocytes in the mesenteric lymph nodes, suggesting that there was no preferential accumulation of these cells in this organ. Secretion of IL-2 by activated T lymphocytes was decreased by the OUA, explaining at least in part the reduction of Tregs, since this cytokine is involved in the peripheral conversion and maintenance of Tregs. CONCLUSION The impact of this reduction in autoimmune diseases, allergy and cancer as well as the potential use of OUA as a therapeutic approach in tumor treatment still needs more investigation.
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Affiliation(s)
- Joyle Moreira Carvalho da Silva
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil
- Programa de Pós Graduação em Patologia Universidade Federal Fluminense, Niterói, Brazil
| | - Augusto das Neves Azevedo
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil
| | | | - Mariana Pires Teixeira
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil
- Programa de Pós Graduação em Patologia Universidade Federal Fluminense, Niterói, Brazil
| | | | - Juliana Fittipaldi
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil
| | - Vinicius Ribeiro Cabral
- Faculdade de Educação, Departamento de Fundamentos Pedagógicos, Universidade Federal Fluminense, Niterói, Brazil
| | - Luciana Souza de Paiva
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil,
- Programa de Pós Graduação em Patologia Universidade Federal Fluminense, Niterói, Brazil,
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17
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Hotta M, Yoshimura H, Satake A, Tsubokura Y, Ito T, Nomura S. GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells. Eur J Immunol 2018; 49:179-191. [PMID: 30457669 DOI: 10.1002/eji.201847684] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 10/08/2018] [Accepted: 11/16/2018] [Indexed: 02/02/2023]
Abstract
Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases, including allogeneic bone marrow transplantation associated with graft-versus-host disease (GVHD). In addition to interleukin-2, Tregs require T-cell receptor and costimulatory signals from antigen-presenting cells, such as DCs, for their optimal proliferation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases DC number and may promote DC-dependent Treg proliferation. Here, we demonstrate that GM-CSF treatment increases CD4+ CD8- DCs, which are associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM-CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both Th1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM-CSF-mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM-CSF induces Treg proliferation by expanding CD4+ CD8- DCs, which in turn regulate alloimmune responses in a cGVHD mouse model. Thus, GM-CSF could be used as a therapeutic DC modulator to induce Treg expansion and to inhibit excessive alloimmune responses in immune-related diseases.
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Affiliation(s)
- Masaaki Hotta
- First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Hideaki Yoshimura
- First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Atsushi Satake
- First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Yukie Tsubokura
- First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
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18
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Abstract
Tight regulation of immune responses is not only critical for preventing autoimmune diseases but also for preventing immunopathological damage during infections in which overactive immune responses may be more harmful for the host than the pathogen itself. Regulatory T cells (Tregs) play a critical role in this regulation, which was discovered using the Friend retrovirus (FV) mouse model. Subsequent FV studies revealed basic biological information about Tregs, including their suppressive activity on effector cells as well as the molecular mechanisms of virus-induced Treg expansion. Treg suppression not only limits immunopathology but also prevents complete elimination of pathogens contributing to chronic infections. Therefore, Tregs play a complex role in the pathogenesis of persistent retroviral infections. New therapeutic concepts to reactivate effector T-cell responses in chronic viral infections by manipulating Tregs also came from work with the FV model. This knowledge initiated many studies to characterize the role of Tregs in HIV pathogenesis in humans, where a complex picture is emerging. On one hand, Tregs suppress HIV-specific effector T-cell responses and are themselves targets of infection, but on the other hand, Tregs suppress HIV-induced immune hyperactivation and thus slow the infection of conventional CD4+ T cells and limit immunopathology. In this review, the basic findings from the FV mouse model are put into perspective with clinical and basic research from HIV studies. In addition, the few Treg studies performed in the simian immunodeficiency virus (SIV) monkey model will also be discussed. The review provides a comprehensive picture of the diverse role of Tregs in different retroviral infections and possible therapeutic approaches to treat retroviral chronicity and pathogenesis by manipulating Treg responses. Regulatory T cells (Tregs) play a very complex role in retroviral infections, and the balance of beneficial versus detrimental effects from Tregs can change between the acute and chronic phase of infection. Therefore, the development of therapeutics to treat chronic retroviral infections via modulation of Tregs requires detailed information regarding both the positive and negative contributions of Tregs in a particular phase of a specific infection. Here, we review the molecular mechanisms that initiate and control Treg responses in retroviral infections as well as the target cells that are functionally manipulated by Tregs. Basic findings from the Friend retrovirus mouse model that initiated this area of research are put into perspective with clinical and basic research from HIV studies. The targeted manipulation of Treg responses holds a bright future for enhancing immune responses to infections, vaccine responses, and for cure or functional cure of chronic retroviral infections.
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Affiliation(s)
- Kim J. Hasenkrug
- Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Claire A. Chougnet
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- * E-mail:
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García-Martínez E, Smith M, Buqué A, Aranda F, de la Peña FA, Ivars A, Cánovas MS, Conesa MAV, Fucikova J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy. Oncoimmunology 2018; 7:e1433982. [PMID: 29872569 PMCID: PMC5980390 DOI: 10.1080/2162402x.2018.1433982] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 01/24/2018] [Indexed: 12/15/2022] Open
Abstract
Cytokines regulate virtually aspects of innate and adaptive immunity, including the initiation, execution and extinction of tumor-targeting immune responses. Over the past three decades, the possibility of using recombinant cytokines as a means to elicit or boost clinically relevant anticancer immune responses has attracted considerable attention. However, only three cytokines have been approved so far by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, namely, recombinant interleukin (IL)-2 and two variants of recombinant interferon alpha 2 (IFN-α2a and IFN-α2b). Moreover, the use of these cytokines in the clinics is steadily decreasing, mostly as a consequence of: (1) the elevated pleiotropism of IL-2, IFN-α2a and IFN-α2b, resulting in multiple unwarranted effects; and (2) the development of highly effective immunostimulatory therapeutics, such as immune checkpoint blockers. Despite this and other obstacles, research in the field continues as alternative cytokines with restricted effects on specific cell populations are being evaluated. Here, we summarize research preclinical and clinical developments on the use of recombinant cytokines for immunostimulation in cancer patients.
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Affiliation(s)
- Elena García-Martínez
- Hematology and Oncology Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | - Melody Smith
- Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Aitziber Buqué
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Fernando Aranda
- Immunoreceptors of the Innate and Adaptive System, IDIBAPS, Barcelona, Spain
| | | | - Alejandra Ivars
- Hematology and Oncology Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | - Manuel Sanchez Cánovas
- Hematology and Oncology Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | | | - Jitka Fucikova
- Sotio, Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Radek Spisek
- Sotio, Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Laurence Zitvogel
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- INSERM, U1015, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France
- Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
| | - Guido Kroemer
- Université Paris Descartes/Paris V, France
- Université Pierre et Marie Curie/Paris VI, Paris
- Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
- Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Université Paris Descartes/Paris V, France
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
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20
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Kennelly KP, Holmes TM, Wallace DM, O'Farrelly C, Keegan DJ. Early Subretinal Allograft Rejection Is Characterized by Innate Immune Activity. Cell Transplant 2017; 26:983-1000. [PMID: 28105976 DOI: 10.3727/096368917x694697] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Successful subretinal transplantation is limited by considerable early graft loss despite pharmacological suppression of adaptive immunity. We postulated that early innate immune activity is a dominant factor in determining graft survival and chose a nonimmunosuppressed mouse model of retinal pigment epithelial (RPE) cell transplantation to explore this. Expression of almost all measured cytokines by DH01 RPE cells increased significantly following graft preparation, and the neutrophil chemoattractant KC/GRO/CINC was most significantly increased. Subretinal allografts of DH01 cells (C57BL/10 origin) into healthy, nonimmunosuppressed C57BL/6 murine eyes were harvested and fixed at 1, 3, 7, and 28 days postoperatively and subsequently cryosectioned and stained. Graft cells were detected using SV40 large T antigen (SV40T) immunolabeling and apoptosis/necrosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Sections were also immunolabeled for macrophage (CD11b and F4/80), neutrophil (Gr1 Ly-6G), and T-lymphocyte (CD3-ɛ) infiltration. Images captured with an Olympus FV1000 confocal microscope were analyzed using the Imaris software. The proportion of the subretinal bolus comprising graft cells (SV40T+) was significantly (p < 0.001) reduced between postoperative day (POD) 3 (90 ± 4%) and POD 7 (20 ± 7%). CD11b+, F4/80+, and Gr1 Ly-6G+ cells increased significantly (p < 0.05) from POD 1 and predominated over SV40T+ cells by POD 7. Colabeling confocal microscopic analysis demonstrated graft engulfment by neutrophils and macrophages at POD 7, and reconstruction of z-stacked confocal images confirmed SV40T inside Gr1 Ly-6G+ cells. Expression of CD3-ɛ was low and did not differ significantly between time points. By POD 28, no graft cells were detectable and few inflammatory cells remained. These studies reveal, for the first time, a critical role for innate immune mechanisms early in subretinal graft rejection. The future success of subretinal transplantation will require more emphasis on techniques to limit innate immune-mediated graft loss, rather than focusing exclusively on suppression of the adaptive immune response.
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21
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Gravano DM, Al-Kuhlani M, Davini D, Sanders PD, Manilay JO, Hoyer KK. CD8 + T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure. J Autoimmun 2016; 75:58-67. [PMID: 27453063 DOI: 10.1016/j.jaut.2016.07.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 07/06/2016] [Accepted: 07/15/2016] [Indexed: 11/24/2022]
Abstract
Bone marrow (BM) failure syndrome encompasses a group of disorders characterized by BM stem cell dysfunction, resulting in varying degrees of hypoplasia and blood pancytopenia, and in many patients is autoimmune and inflammatory in nature. The important role of T helper 1 (Th1) polarized CD4+ T cells in driving BM failure has been clearly established in several models. However, animal model data demonstrating a functional role for CD8+ T cells in BM dysfunction is largely lacking and our objective was to test the hypothesis that CD8+ T cells play a non-redundant role in driving BM failure. Clinical evidence implicates a detrimental role for CD8+ T cells in BM failure and a beneficial role for Foxp3+ regulatory T cells (Tregs) in maintaining immune tolerance in the BM. We demonstrate that IL-2-deficient mice, which have a deficit in functional Tregs, develop spontaneous BM failure. Furthermore, we demonstrate a critical role for CD8+ T cells in the development of BM failure, which is dependent on the cytokine, IFNγ. CD8+ T cells promote hematopoietic stem cell dysfunction and depletion of myeloid lineage progenitor cells, resulting in anemia. Adoptive transfer experiments demonstrate that CD8+ T cells dramatically expedite disease progression and promote CD4+ T cell accumulation in the BM. Thus, BM dysregulation in IL-2-deficient mice is mediated by a Th1 and IFNγ-producing CD8+ T cell (Tc1) response.
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Affiliation(s)
- David M Gravano
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA
| | - Mufadhal Al-Kuhlani
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA
| | - Dan Davini
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA
| | - P Dominick Sanders
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA
| | - Jennifer O Manilay
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA; Health Sciences Research Institute, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA
| | - Katrina K Hoyer
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA; Health Sciences Research Institute, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
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22
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Huijts CM, Santegoets SJ, Quiles Del Rey M, de Haas RR, Verheul HM, de Gruijl TD, van der Vliet HJ. Differential effects of inhibitors of the PI3K/mTOR pathway on the expansion and functionality of regulatory T cells. Clin Immunol 2016; 168:47-54. [PMID: 27189717 DOI: 10.1016/j.clim.2016.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 04/11/2016] [Accepted: 05/13/2016] [Indexed: 12/23/2022]
Abstract
The PI3K/mTOR pathway is commonly deregulated in cancer. mTOR inhibitors are registered for the treatment of several solid tumors and novel inhibitors are explored clinically. Notably, this pathway also plays an important role in immunoregulation. While mTOR inhibitors block cell cycle progression of conventional T cells (Tconv), they also result in the expansion of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Tregs), and this likely limits their clinical antitumor efficacy. Here, we compared the effects of dual mTOR/PI3K inhibition (using BEZ235) to single PI3K (using BKM120) or mTOR inhibition (using rapamycin and everolimus) on Treg expansion and functionality. Whereas rapamycin, everolimus and BEZ235 effected a relative expansion benefit for Tregs and increased their overall suppressive activity, BKM120 allowed for similar expansion rates of Tregs and Tconv without altering their overall suppressive activity. Therefore, PI3K inhibition alone might offer antitumor efficacy without the detrimental selective expansion of Tregs associated with mTOR inhibition.
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Affiliation(s)
- Charlotte M Huijts
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
| | - Saskia J Santegoets
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Maria Quiles Del Rey
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Richard R de Haas
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Henk M Verheul
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Tanja D de Gruijl
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Hans J van der Vliet
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
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23
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Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N. Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2016; 22:2195-205. [PMID: 26900284 PMCID: PMC4734996 DOI: 10.3748/wjg.v22.i7.2195] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 11/11/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.
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24
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Ren B, McKinstry WJ, Pham T, Newman J, Layton DS, Bean AG, Chen Z, Laurie KL, Borg K, Barr IG, Adams TE. Structural and functional characterisation of ferret interleukin-2. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2016; 55:32-38. [PMID: 26472619 PMCID: PMC7102629 DOI: 10.1016/j.dci.2015.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/07/2015] [Accepted: 10/07/2015] [Indexed: 06/05/2023]
Abstract
While the ferret is a valuable animal model for a number of human viral infections, such as influenza, Hendra and Nipah, evaluating the cellular immune response following infection has been hampered by the lack of a number of species-specific immunological reagents. Interleukin 2 (IL-2) is one such key cytokine. Ferret recombinant IL-2 incorporating a C-terminal histidine tag was expressed and purified and the three-dimensional structure solved and refined at 1.89 Å by X-ray crystallography, which represents the highest resolution and first non-human IL-2 structure. While ferret IL-2 displays the classic cytokine fold of the four-helix bundle structure, conformational flexibility was observed at the second helix and its neighbouring region in the bundle, which may result in the disruption of the spatial arrangement of residues involved in receptor binding interactions, implicating subtle differences between ferret and human IL-2 when initiating biological functions. Ferret recombinant IL-2 stimulated the proliferation of ferret lymph node cells and induced the expression of mRNA for IFN-γ and Granzyme A.
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Affiliation(s)
- Bin Ren
- CSIRO Manufacturing, Parkville, VIC 3052, Australia
| | | | - Tam Pham
- CSIRO Manufacturing, Parkville, VIC 3052, Australia
| | - Janet Newman
- CSIRO Manufacturing, Parkville, VIC 3052, Australia
| | | | - Andrew G Bean
- CSIRO Health and Biosecurity, Geelong, VIC 3219, Australia
| | - Zhenjun Chen
- Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute, Melbourne, VIC 3000, Australia
| | - Karen L Laurie
- WHO Collaborating Centre for Reference and Research on Influenza (VIDRL), Peter Doherty Institute for Infection & Immunity, Melbourne, Australia
| | - Kathryn Borg
- WHO Collaborating Centre for Reference and Research on Influenza (VIDRL), Peter Doherty Institute for Infection & Immunity, Melbourne, Australia
| | - Ian G Barr
- WHO Collaborating Centre for Reference and Research on Influenza (VIDRL), Peter Doherty Institute for Infection & Immunity, Melbourne, Australia
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Nogueira JDS, Canto FBD, Nunes CFCG, Vianna PHO, Paiva LDS, Nóbrega A, Bellio M, Fucs R. Enhanced renewal of regulatory T cells in relation to CD4(+) conventional T lymphocytes in the peripheral compartment. Immunology 2015; 147:221-39. [PMID: 26572097 DOI: 10.1111/imm.12555] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/16/2015] [Accepted: 11/06/2015] [Indexed: 12/16/2022] Open
Abstract
CD4(+) Foxp3(+) regulatory T (Treg) cells are necessary for the maintenance of self-tolerance and T-cell homeostasis. This population is kept at stable frequencies in secondary lymphoid organs for the majority of the lifetime, despite permanent thymic emigration or in the face of thymic involution. Continuous competition is expected to occur between recently thymus-emigrated and resident Treg cells (either natural or post-thymically induced). In the present work, we analysed the renewal dynamics of Treg cells compared with CD4(+) Foxp3- conventional T cells (Tconv), using protocols of single or successive T-cell transfers into syngeneic euthymic or lymphopenic (nu/nu or RAG2(-/-)) mice, respectively. Our results show a higher turnover for Treg cells in the peripheral compartment, compared with Tconv cells, when B cell-sufficient euthymic or nude hosts are studied. This increased renewal within the Treg pool, shown by the greater replacement of resident Treg cells by donor counterparts, correlates with augmented rates of proliferation and is not modified following temporary environmental perturbations induced by inflammatory state or microbiota alterations. Notably, the preferential substitution of Treg lymphocytes was not observed in RAG2(-/-) hosts. We showed that limited B-cell replenishment in the RAG2(-/-) hosts decisively contributed to the altered peripheral T-cell homeostasis. Accordingly, weekly transfers of B cells to RAG2(-/-) hosts rescued the preferential substitution of Treg lymphocytes. Our study discloses a new aspect of T-cell homeostasis that depends on the presence of B lymphocytes to regulate the relative incorporation of recently arrived Treg and Tconv cells in the peripheral compartment.
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Affiliation(s)
- Jeane de Souza Nogueira
- Departamento de Imunologia, Instituto de Microbiologia Paulo de Goés (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fábio Barrozo do Canto
- Departamento de Imunologia, Instituto de Microbiologia Paulo de Goés (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Caroline Fraga Cabral Gomes Nunes
- Departamento de Imunologia, Instituto de Microbiologia Paulo de Goés (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro Henrique Oliveira Vianna
- Departamento de Imunologia, Instituto de Microbiologia Paulo de Goés (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luciana de Souza Paiva
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - Alberto Nóbrega
- Departamento de Imunologia, Instituto de Microbiologia Paulo de Goés (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Bellio
- Departamento de Imunologia, Instituto de Microbiologia Paulo de Goés (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rita Fucs
- Departamento de Imunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Rio de Janeiro, Brazil
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Nie J, Li YY, Zheng SG, Tsun A, Li B. FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases. Front Immunol 2015; 6:493. [PMID: 26441996 PMCID: PMC4585344 DOI: 10.3389/fimmu.2015.00493] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 09/09/2015] [Indexed: 01/22/2023] Open
Abstract
CD4+CD25+ regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases.
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Affiliation(s)
- Jia Nie
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China
| | - Yang Yang Li
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China
| | - Song Guo Zheng
- Clinical Immunology Center, The Third Affiliated Hospital, Sun Yat-Sen University , Guangzhou , China ; Department of Medicine, Division of Rheumatology, Penn State Hershey College of Medicine , Hershey, PA , USA
| | - Andy Tsun
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China ; Innovent Biologics Inc. , Suzhou , China
| | - Bin Li
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China
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27
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Wang T, Sun X, Zhao J, Zhang J, Zhu H, Li C, Gao N, Jia Y, Xu D, Huang FP, Li N, Lu L, Li ZG. Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood. Ann Rheum Dis 2015; 74:1293-301. [PMID: 24521740 DOI: 10.1136/annrheumdis-2013-204228] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 01/24/2014] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Regulatory T cells (Tregs) with the plasticity of producing proinflammatory cytokine IL-17 have been demonstrated under normal and pathogenic conditions. However, it remains unclear whether IL-17-producing Tregs lose their suppressive functions because of their plasticity toward Th17 in autoimmunity. The aim of this study was to investigate IL-17-producing Tregs from patients with rheumatoid arthritis (RA), and characterise their regulatory capacity and clinical significance. METHODS Foxp3 and IL-17 coexpression were evaluated in CD4 T lymphocytes from RA patients. An in vitro T cell polarisation assay was performed to investigate the role of proinflammatory cytokines in IL-17-producing Treg polarisation. The suppressive function of IL-17-producing Tregs in RA was assessed by an in vitro suppression assay. The relationship between this Treg subset and clinical features in RA patients was analysed using Spearman's rank correlation test. RESULTS A higher frequency of IL-17-producing Tregs was present in the peripheral blood of RA patients compared with healthy subjects. These cells from peripheral blood showed phenotypic characteristics of Th17 and Treg cells, and suppressed T cell proliferation in vitro. Tregs in RA synovial fluid lost suppressive function. The Th17 plasticity of Tregs could be induced by IL-6 and IL-23. An increased ratio of this Treg subset was associated with decreased levels of inflammatory markers, including the erythrocyte sedimentation rate and C-reactive protein level, in patients with RA. CONCLUSIONS Increased levels of IL-17-producing Tregs were identified in RA patients. This Treg subset with Th17 plasticity in peripheral blood retained suppressive functions and was associated with milder inflammatory conditions, suggesting that this Treg population works as a negative regulator in RA, but in RA synovial site it may be pathogenic.
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Affiliation(s)
- Tian Wang
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China Department of Rheumatology & Immunology, Beijing An Zhen Hospital, Capital Medical University, Beijing, China
| | - Xiaolin Sun
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
| | - Jing Zhao
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
| | - Jing Zhang
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
| | - Huaqun Zhu
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
| | - Chun Li
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
| | - Na Gao
- Department of Rheumatology & Immunology, Beijing An Zhen Hospital, Capital Medical University, Beijing, China
| | - Yuan Jia
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
| | - Dakang Xu
- MIMR-PHI Institute of Medical Research, Monash University, Clayton, Victoria, Australia and Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China
| | - Fang-Ping Huang
- Division of Immunology & Inflammation (Rheumatology Section), Department of Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK
| | - Ningli Li
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liwei Lu
- Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China
| | - Zhan-Guo Li
- Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing, China
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28
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Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat Immunol 2015; 16:628-34. [DOI: 10.1038/ni.3150] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/17/2015] [Indexed: 12/14/2022]
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Simonetta F, Gestermann N, Bloquet S, Bourgeois C. Interleukin-7 optimizes FOXP3+CD4+ regulatory T cells reactivity to interleukin-2 by modulating CD25 expression. PLoS One 2014; 9:e113314. [PMID: 25485946 PMCID: PMC4259569 DOI: 10.1371/journal.pone.0113314] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 10/22/2014] [Indexed: 12/04/2022] Open
Abstract
The vast majority of Foxp3 regulatory T cells (Treg) exhibits constitutive expression of CD25 (IL-2Rα), which allows the constitution of the high affinity IL-2Rαβγ receptor, ensuring efficient IL-2 binding by Treg. Maintenance of CD25 expression at Treg surface depends on both cell intrinsic factors and environmental stimuli such as IL-2 itself. Whether other factors can participate to maintenance of CD25 expression in vivo is at present unknown. In the present work we demonstrated that IL-7, a gamma-chain cytokine exerting a crucial role in T cell development and homeostasis, is able and necessary to sustain the expression of high levels of CD25 at Treg surface. We demonstrated that, during in vitro cultures performed in the absence of IL-2, IL-7 is able to sustain CD25 expression at Treg surface through a transcriptional mechanism. By studying mice in which IL-7 signaling is either genetically impaired or increased and by employing adoptive transfer murine models, we demonstrated that IL-7 is necessary for sustained expression of CD25 at Treg surface in vivo. To ascertain the biological impact of IL-7 mediated modulation of CD25 expression, we demonstrated that IL-7 modulation of CD25 expression at Treg surface affected their ability to efficiently bind IL-2 and transduce IL-2 signaling. Finally, we demonstrated that IL-7 dependent modulation of CD25 associated with potentiated IL-2 induced expansion of Treg in vivo. Collectively, our results identify IL-7 as a necessary factor contributing to sustained CD25 expression at Treg surface in vivo thereby affecting their ability to efficiently react to IL-2.
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Affiliation(s)
- Federico Simonetta
- INSERM, U1012, Le Kremlin-Bicêtre, France
- Univ Paris-SUD, UMR-S1012, Le Kremlin-Bicêtre, France
- Division of Hematology, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland
| | - Nicolas Gestermann
- INSERM, U1012, Le Kremlin-Bicêtre, France
- Univ Paris-SUD, UMR-S1012, Le Kremlin-Bicêtre, France
| | - Stéphane Bloquet
- Animalerie centrale, Faculté de Médecine Paris-Sud, Univ Paris-Sud, Le Kremlin-Bicêtre, France
| | - Christine Bourgeois
- INSERM, U1012, Le Kremlin-Bicêtre, France
- Univ Paris-SUD, UMR-S1012, Le Kremlin-Bicêtre, France
- * E-mail:
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30
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Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease. Immunol Lett 2014; 162:173-84. [PMID: 25445496 DOI: 10.1016/j.imlet.2014.10.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 10/21/2014] [Accepted: 10/27/2014] [Indexed: 12/28/2022]
Abstract
Low-dose IL-2 administration can control autoimmunity by specifically activating CD4(+) Foxp3(+) regulatory T cells (Tregs). Here, we studied IL-2-based immunotherapy in experimental graft-versus-host disease (GVHD). IL-2 administration to donor mice induced a dose-dependent expansion of Tregs in the graft but was insufficient to control GVHD. IL-2 administration to allogeneic-grafted recipient mice activated T-conventional cells (Tcons) and did not prevent GVHD. This loss of IL-2 selectivity toward Tregs was explained by an IL-2-induced increase in the IL-2 receptor α-chain expression on Tcons. Finally, in xeno-GVHD generated by human PBMCs transplanted into immunodeficient mice, low-dose IL-2 increased Treg frequencies but did neither control pro-inflammatory cytokine production by pathogenic Tcons, nor prevented GVHD. Furthermore, combination of low-dose IL-2 with rapamycin was ineffective in this model. Our results indicate that limitations on the use of IL-2 during acute GVHD are likely due to the massive activation of the allogeneic T cells unique to this setting.
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31
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Chambers ES, Suwannasaen D, Mann EH, Urry Z, Richards DF, Lertmemongkolchai G, Hawrylowicz CM. 1α,25-dihydroxyvitamin D3 in combination with transforming growth factor-β increases the frequency of Foxp3⁺ regulatory T cells through preferential expansion and usage of interleukin-2. Immunology 2014; 143:52-60. [PMID: 24673126 PMCID: PMC4137955 DOI: 10.1111/imm.12289] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 02/28/2014] [Accepted: 03/19/2014] [Indexed: 01/22/2023] Open
Abstract
A high prevalence of vitamin D insufficiency and deficiency exists worldwide, which is associated with an increased incidence and severity of a range of immune-mediated diseases. This has resulted in considerable interest in the immunodulatory functions of vitamin D. The active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to increase the frequency of Foxp3+ CD4+ T regulatory (Treg) cells when present at high concentrations or under strong T-cell stimulation in culture. Supporting evidence exists in vivo for a positive association between serum 25(OH)D and Foxp3+ Treg cell numbers in humans. The aim of this work was to identify the cytokine milieu required in vitro to promote Foxp3+ Treg cells in cultures containing 1,25(OH)2D3 at more moderate concentrations (10−7 m). Stimulation of human CD4+ T cells with a combination of 1,25(OH)2D3 and transforming growth factor-β (TGF-β) greatly increased the frequency of Foxp3+ Treg cells, which is proposed to result from the preferential expansion of Foxp3+ Treg cells, as compared with the Foxp3− effector T cells, in culture. The differential effect on proliferation may result from enhanced availability and usage of interleukin-2 by the Foxp3+ Treg cells compared with Foxp3− effector T cells. In summary, modulation of the cytokine environment to one high in TGF-β in the presence of 1,25(OH)2D3 (10−7 m) significantly increased Foxp3+ Treg cell frequency. These data provide additional evidence for the important immunomodulatory properties of 1,25(OH)2D3 that exist and may help to control inflammatory diseases.
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Affiliation(s)
- Emma S Chambers
- MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK
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32
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Trzonkowski P, Dukat-Mazurek A, Bieniaszewska M, Marek-Trzonkowska N, Dobyszuk A, Juścińska J, Dutka M, Myśliwska J, Hellmann A. Treatment of graft-versus-host disease with naturally occurring T regulatory cells. BioDrugs 2014; 27:605-14. [PMID: 23813436 PMCID: PMC3832760 DOI: 10.1007/s40259-013-0050-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
A significant body of evidence suggests that treatment with naturally occurring CD4+CD25+ T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment.
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Affiliation(s)
- Piotr Trzonkowski
- Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Ul. Dębinki 1, 80-211, Gdańsk, Poland,
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Co-expression of tumor antigen and interleukin-2 from an adenoviral vector augments the efficiency of therapeutic tumor vaccination. Mol Ther 2014; 22:2107-2117. [PMID: 25023330 DOI: 10.1038/mt.2014.130] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 06/22/2014] [Indexed: 12/14/2022] Open
Abstract
We have previously shown that for the majority of antigens, adenoviral vaccines expressing the target antigen fused to the MHC associated invariant chain (Ii) induce an accelerated, augmented, and prolonged transgene-specific CD8(+) T-cell response. Here we describe a new adenoviral vaccine vector approach where the target antigen fused to Ii is expressed from the adenoviral E1 region and IL-2 is expressed from the E3 region. Immunization of mice with this new vector construct resulted in an augmented primary effector CD8(+) T-cell response. Furthermore, in a melanoma model we observed significantly prolonged tumor control in vaccinated wild type (WT) mice. The improved tumor control required antigen-specific cells, since no tumor control was observed, unless the melanoma cells expressed the vaccine targeted antigen. We also tested our new vaccine in immunodeficient (CD80/86 deficient) mice. Following vaccination with the IL-2 expressing construct, these mice were able to raise a delayed but substantial CD8(+) T-cell response, and to control melanoma growth nearly as efficaciously as similarly vaccinated WT mice. Taken together, these results demonstrate that current vaccine vectors can be improved and even tailored to meet specific demands: in the context of therapeutic vaccination, the capacity to promote an augmented effector T-cell response.
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34
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Cabello-Kindelan C, de la Barrera A, Malek TR, Bayer AL. In vivo environment necessary to support transplanted donor mouse T regulatory cells. Am J Transplant 2014; 14:1032-45. [PMID: 24618297 DOI: 10.1111/ajt.12650] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/06/2013] [Accepted: 12/26/2013] [Indexed: 01/25/2023]
Abstract
CD4(+) Foxp3(+) T regulatory cells (Tregs ) are essential for maintaining immunological tolerance, which could be harnessed for novel cell-based therapies to prevent allograft rejection and control autoimmunity. However, the use of Tregs for therapy is hindered by the inability to generate sufficient cell numbers to inhibit desired immune response(s) and achieve stable engraftment of the donor-Treg cell inoculums. The present study was undertaken to investigate the in vivo requirements to promote engraftment of adoptively transferred Tregs and induce tolerance. We established that not only is peripheral space required, but competition from endogenous Tregs must be minimized for successful donor-Treg engraftment with IL-2 critical for driving their proliferation and survival. Moreover, these studies revealed a critical level of donor-Treg engraftment was required for tolerance induction to skin transplants. These mouse studies lay the foundation for development of novel Treg approaches for tolerance induction in the clinic involving not only organ or cellular transplantation, but also to re-establish self-tolerance in autoimmune settings.
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Affiliation(s)
- C Cabello-Kindelan
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
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35
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Tabares P, Berr S, Römer PS, Chuvpilo S, Matskevich AA, Tyrsin D, Fedotov Y, Einsele H, Tony H, Hünig T. Human regulatory T cells are selectively activated by low‐dose application of the CD28 superagonist TGN1412/TAB08. Eur J Immunol 2014; 44:1225-36. [DOI: 10.1002/eji.201343967] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 11/28/2013] [Accepted: 12/23/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Paula Tabares
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
| | - Susanne Berr
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
| | - Paula S. Römer
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
- TheraMAB LLC Würzburg Germany
| | | | | | | | | | - Hermann Einsele
- Department of Internal Medicine II University Hospital of Würzburg Würzburg Germany
| | - Hans‐Peter Tony
- Department of Internal Medicine II University Hospital of Würzburg Würzburg Germany
| | - Thomas Hünig
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
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36
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Lin CH, Zhang W, Ng TW, Zhang D, Jiang J, Pulikkottil B, Lakkis F, Gorantla VS, Lee WPA, Brandacher G, Zheng XX. Vascularized osteomyocutaneous allografts are permissive to tolerance by induction-based immunomodulatory therapy. Am J Transplant 2013; 13:2161-8. [PMID: 23718897 DOI: 10.1111/ajt.12275] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 03/27/2013] [Accepted: 03/28/2013] [Indexed: 01/25/2023]
Abstract
Vascularized composite allografts (VCAs) are unique among transplanted organs in that they are composed of multiple tissues with disparate antigenic and immunologic properties. As the predominant indications for VCAs are non-life-threatening conditions, there is an immediate need to develop tolerance induction strategies and to elucidate the mechanisms of VCA rejection and tolerance using VCA-specific animal models. In this study, we explore the effects of in vitro induced donor antigen-specific CD4(-) CD8(-) double negative (DN) Treg-based therapy, in a fully MHC mismatched mouse VCA such as a vascularized osteomyocutaneous as compared to a non-VCA such as a full thickness skin (FTS) transplantation model to elucidate the unique features of VCA rejection and tolerance. We demonstrate that combined therapy with antigen-induced CD4 derived DN Tregs and a short course of anti-lymphocyte serum, rapamycin and IL-2/Fc fusion protein results in donor-specific tolerance to VCA, but not FTS allografts. Macrochimerism was detected in VCA but not FTS allograft recipients up to >60 days after transplantation. Moreover, a significant increase of CD4(+) Foxp3(+) Tregs was found in the peripheral blood of tolerant VCA recipients. These data suggest that VCA are permissive to tolerance induced by DN Treg-based induction therapy.
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Affiliation(s)
- C H Lin
- Department of Plastic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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37
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Povoleri GAM, Scottà C, Nova-Lamperti EA, John S, Lombardi G, Afzali B. Thymic versus induced regulatory T cells - who regulates the regulators? Front Immunol 2013; 4:169. [PMID: 23818888 PMCID: PMC3694260 DOI: 10.3389/fimmu.2013.00169] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 06/13/2013] [Indexed: 01/07/2023] Open
Abstract
Physiological health must balance immunological responsiveness against foreign pathogens with tolerance toward self-components and commensals. Disruption of this balance causes autoimmune diseases/chronic inflammation, in case of excessive immune responses, and persistent infection/immunodeficiency if regulatory components are overactive. This homeostasis occurs at two different levels: at a resting state to prevent autoimmune disease, as autoreactive effector T-cells (Teffs) are only partially deleted in the thymus, and during inflammation to prevent excessive tissue injury, contract the immune response, and enable tissue repair. Adaptive immune cells with regulatory function (“regulatory T-cells”) are essential to control Teffs. Two sets of regulatory T cell are required to achieve the desired control: those emerging de novo from embryonic/neonatal thymus (“thymic” or tTregs), whose function is to control autoreactive Teffs to prevent autoimmune diseases, and those induced in the periphery (“peripheral” or pTregs) to acquire regulatory phenotype in response to pathogens/inflammation. The differentiation mechanisms of these cells determine their commitment to lineage and plasticity toward other phenotypes. tTregs, expressing high levels of IL-2 receptor alpha chain (CD25), and the transcription factor Foxp3, are the most important, since mutations or deletions in these genes cause fatal autoimmune diseases in both mice and men. In the periphery, instead, Foxp3+ pTregs can be induced from naïve precursors in response to environmental signals. Here, we discuss molecular signatures and induction processes, mechanisms and sites of action, lineage stability, and differentiating characteristics of both Foxp3+ and Foxp3− populations of regulatory T cells, derived from the thymus or induced peripherally. We relate these predicates to programs of cell-based therapy for the treatment of autoimmune diseases and induction of tolerance to transplants.
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Affiliation(s)
- Giovanni Antonio Maria Povoleri
- Medical Research Council Centre for Transplantation, King's College London , London , UK ; National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London , London , UK
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38
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Shen X, Niu C, König R. Increased numbers and suppressive activity of regulatory CD25(+)CD4(+) T lymphocytes in the absence of CD4 engagement by MHC class II molecules. Cell Immunol 2013; 282:117-28. [PMID: 23770721 DOI: 10.1016/j.cellimm.2013.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 04/26/2013] [Accepted: 05/06/2013] [Indexed: 11/28/2022]
Abstract
Mechanisms of central and peripheral tolerance prevent autoimmunity. Regulatory T cells inhibit the activation of potentially auto-reactive T cells in peripheral lymphoid organs. In transgenic mice in which all MHC class II molecules are incapable of binding to CD4, class II MHC-restricted T cells preferentially differentiated into immunosuppressive, regulatory T cells. In these mutant MHC class II transgenic mice, a subset of CD4(+) T cells constitutively expressed moderately elevated levels of CD25 and potently inhibited interleukin-2 secretion by T cells from normal mice in a cell-to-cell, contact-dependent manner. Immunosuppressive activity depended on activation of the regulatory T cells. Thus, CD25(+)CD4(+) T cells from mutant MHC class II transgenic mice resembled phenotypically and functionally a major subset of natural regulatory T cells in normal mice, but were two to three-times more abundant. These results further clarify the mechanisms that govern the differentiation and maintenance of CD25(+)CD4(+) regulatory T cells, and present avenues for immunomodulation.
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Affiliation(s)
- Xiaoli Shen
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA
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Myers L, Joedicke JJ, Carmody AB, Messer RJ, Kassiotis G, Dudley JP, Dittmer U, Hasenkrug KJ. IL-2-independent and TNF-α-dependent expansion of Vβ5+ natural regulatory T cells during retrovirus infection. THE JOURNAL OF IMMUNOLOGY 2013; 190:5485-95. [PMID: 23645880 DOI: 10.4049/jimmunol.1202951] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Friend virus infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic infection. Adoptive transfer experiments and the expression of neuropilin-1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4(+) T cells that converted into induced Tregs. Analysis of Treg TCR Vβ chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the Vβ5(+) Treg subset, which is known to be responsive to endogenous retrovirus-encoded superantigens. In contrast to the major population of Tregs, the Vβ5(+) subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8(+) T cell response rather than the level of Friend virus infection. Surprisingly, the expansion and accumulation of the Vβ5(+) Tregs was IL-2 independent but dependent on TNF-α. These experiments reveal a subset-specific Treg induction by a new pathway.
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Affiliation(s)
- Lara Myers
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
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Composite tissue allotransplantation immunology. Arch Plast Surg 2013; 40:141-53. [PMID: 23529264 PMCID: PMC3605559 DOI: 10.5999/aps.2013.40.2.141] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 01/08/2013] [Accepted: 01/09/2013] [Indexed: 01/20/2023] Open
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Vogel I, Verbinnen B, Maes W, Boon L, Van Gool SW, Ceuppens JL. Foxp3+ regulatory T cells are activated in spite of B7-CD28 and CD40-CD40L blockade. Eur J Immunol 2013; 43:1013-23. [PMID: 23348953 DOI: 10.1002/eji.201242737] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 12/11/2012] [Accepted: 01/21/2013] [Indexed: 01/01/2023]
Abstract
Costimulatory signals are required for priming and activation of naive T cells, while it is less clear how they contribute to induction of regulatory T (Treg)-cell activity. We previously reported that the blockade of the B7-CD28 and CD40L-CD40 interaction efficiently suppresses allogeneic T-cell activation in vivo. This was characterized by an initial rise in Foxp3(+) cells, followed by depletion of host-reactive T cells. To further investigate effects of costimulatory blockade on Treg cells, we used an in vitro model of allogeneic CD4(+) cell activation. When CTLA-4Ig and anti-CD40L mAb (MR1) were added to the cultures, T-cell proliferation and IL-2 production were strongly reduced. However, Foxp3(+) cells proliferated and acquired suppressive activity. They suppressed activation of syngeneic CD4(+) cells much more efficiently than did freshly isolated Treg cells. CD4(+) cells activated by allogeneic cells in the presence of MR1 and CTLA-4Ig were hyporesponsive on restimulation, but their response was restored to that of naive CD4(+) cells when Foxp3(+) Treg cells were removed. We conclude that natural Treg cells are less dependent on B7-CD28 or CD40-CD40L costimulation compared with Foxp3(-) T cells. Reduced costimulation therefore alters the balance between Teff and Treg-cell activation in favor of Treg-cell activity.
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Affiliation(s)
- Isabel Vogel
- Laboratory of Clinical Immunology, Faculty of Medicine, KU Leuven, Leuven, Belgium
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42
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Wachstein J, Tischer S, Figueiredo C, Limbourg A, Falk C, Immenschuh S, Blasczyk R, Eiz-Vesper B. HSP70 enhances immunosuppressive function of CD4(+)CD25(+)FoxP3(+) T regulatory cells and cytotoxicity in CD4(+)CD25(-) T cells. PLoS One 2012; 7:e51747. [PMID: 23300563 PMCID: PMC3530531 DOI: 10.1371/journal.pone.0051747] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 11/05/2012] [Indexed: 11/19/2022] Open
Abstract
Human CD4+CD25+FoxP3+ T regulatory cells (Tregs) control effector T cells and play a central role in peripheral tolerance and immune homeostasis. Heat shock protein 70 (HSP70) is a major immunomodulatory molecule, but its effect on the functions of Tregs is not well understood. To investigate target-dependent and –independent Treg functions, we studied cytokine expression, regulation of proliferation and cytotoxicity after exposure of Tregs to HSP70. HSP70-treated Tregs significantly inhibited proliferation of CD4+CD25− target cells and downregulated the secretion of the proinflammatory cytokines IFN-γ and TNF-α. By contrast, HSP70 increased the secretion of Treg suppressor cytokines IL-10 and TGF-β. Treatment with HSP70 enhanced the cytotoxic properties of Tregs only to a minor extent (4-fold), but led to stronger responses in CD4+CD25− cells (42-fold). HSP70-induced modulation of T-cell responses was further enhanced by combined treatment with HSP70 plus IL-2. Treatment of Tregs with HSP70 led to phosphorylation of PI3K/AKT and the MAPKs JNK and p38, but not that of ERK1/2. Exposure of Tregs to specific inhibitors of PI3K/AKT and the MAPKs JNK and p38 reduced the immunosuppressive function of HSP70-treated Tregs as indicated by the modified secretion of specific target cell (IFN-γ, TNF-α) and suppressor cytokines (IL-10, TGF-β). Taken together, the data show that HSP70 enhances the suppressive capacity of Tregs to neutralize target immune cells. Thus HSP70-enhanced suppression of Tregs may prevent exaggerated immune responses and may play a major role in maintaining immune homeostasis.
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Affiliation(s)
- Julian Wachstein
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Sabine Tischer
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Constanca Figueiredo
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
- Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Anne Limbourg
- Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
- Department of Plastic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Christine Falk
- Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
- Institute for Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
- Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Britta Eiz-Vesper
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
- Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
- * E-mail:
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Langenhorst D, Gogishvili T, Ribechini E, Kneitz S, McPherson K, Lutz MB, Hünig T. Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells. PLoS One 2012; 7:e50080. [PMID: 23226238 PMCID: PMC3511437 DOI: 10.1371/journal.pone.0050080] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 10/16/2012] [Indexed: 11/18/2022] Open
Abstract
The ability of CD4(+)Foxp3(+) regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7(+)CCR5(-) lymph node-seeking to a CCR7(-)CCR5(+) inflammation-seeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.
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MESH Headings
- Animals
- Antibodies/immunology
- Antibodies/pharmacology
- Apoptosis/drug effects
- CD28 Antigens/agonists
- CD28 Antigens/immunology
- Cell Differentiation/drug effects
- Cell Movement/drug effects
- Cells, Cultured
- Clone Cells
- Gene Expression/drug effects
- Inflammation/immunology
- Inflammation/metabolism
- Interleukin-10/biosynthesis
- Interleukin-10/immunology
- Lymph Nodes/cytology
- Lymph Nodes/drug effects
- Lymph Nodes/immunology
- Lymphocyte Activation/drug effects
- Mice
- Mice, Inbred C57BL
- Receptors, CCR5/genetics
- Receptors, CCR5/immunology
- Receptors, CCR7/genetics
- Receptors, CCR7/immunology
- T-Lymphocytes, Cytotoxic/cytology
- T-Lymphocytes, Cytotoxic/drug effects
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Regulatory/cytology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
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Affiliation(s)
- Daniela Langenhorst
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Tea Gogishvili
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Eliana Ribechini
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Susanne Kneitz
- Interdisciplinary Centre for Clinical Research (IZKF), University of Würzburg, Würzburg, Germany
| | - Kirsty McPherson
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia
| | - Manfred B. Lutz
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Thomas Hünig
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
- * E-mail:
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Triplett TA, Curti BD, Bonafede PR, Miller WL, Walker EB, Weinberg AD. Defining a functionally distinct subset of human memory CD4+ T cells that are CD25POS and FOXP3NEG. Eur J Immunol 2012; 42:1893-905. [PMID: 22585674 DOI: 10.1002/eji.201242444] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Surface expression of the IL-2 receptor α-chain (CD25) has been used to discriminate between CD4(+) CD25(HI) FOXP3(+) regulatory T (Treg) cells and CD4(+) CD25(NEG) FOXP3(-) non-Treg cells. However, this study reports that the majority of resting human memory CD4(+) FOXP3(-) T cells expresses intermediate levels of CD25 and that CD25 expression can be used to delineate a functionally distinct memory subpopulation. The CD25(NEG) memory T-cell population contains the vast majority of late differentiated cells that respond to antigens associated with chronic immune responses and are increased in patients with systemic lupus erythematosus (SLE). In contrast, the CD25(INT) memory T cells respond to antigens associated with recall responses, produce a greater array of cytokines, and are less dependent on costimulation for effector responses due to their expression of CD25. Lastly, compared to the CD25(NEG) and Treg-cell populations, the CD25(INT) memory population is lost to a greater degree from the blood of cancer patients treated with IL-2. Collectively, these results show that in humans, a large proportion of CD4(+) memory T cells express intermediate levels of CD25, and this CD25(INT) FOXP3(-) subset is a functionally distinct memory population that is uniquely affected by IL-2.
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Affiliation(s)
- Todd A Triplett
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA
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Kulhankova K, Rouse T, Nasr ME, Field EH. Dendritic cells control CD4+CD25+ Treg cell suppressor function in vitro through juxtacrine delivery of IL-2. PLoS One 2012; 7:e43609. [PMID: 22984435 PMCID: PMC3440416 DOI: 10.1371/journal.pone.0043609] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 07/26/2012] [Indexed: 12/12/2022] Open
Abstract
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) restrict inflammatory responses to self and nonself. Aberrant Treg activity is pathologic: Insufficient Treg activity is implicated in autoimmunity, allergy, and graft-versus-host-disease; overabundant activity is implicated in chronic infection and cancer. Tregs require IL-2 for their expansion and acquisition/execution of suppressor function; however, because Tregs cannot produce IL-2, they depend on IL-2 from an exogenous source. Until now, that IL-2 source had not been established. We asked whether dendritic cells (DCs) could supply IL-2 to Tregs and, if so, what was required for that delivery. We used flow cytometry, IL-2 ELISPOT, RT-qPCR, and IL-2 promoter-driven reporter assays to measure intracytoplasmic IL-2, secreted protein, IL-2 message and IL-2 promoter activity in bone marrow-derived (BMDC) and splenic DCs. We examined conjugate formation between Tregs, conventional CD4(+) cells, and IL-2-expressing DCs. We measured Treg levels of CD25, Foxp3, and suppressor function after co-culture with IL-2 sufficient and IL-2(-/-) DCs. We generated IL-2-mCherry-expressing DCs and used epifluorescence microscopy and flow cytometry to track IL-2 transfer to Tregs and test requirements for transfer. Between 0.7 to 2.4% of DCs constitutively produced IL-2 and diverted IL-2 secretion to Tregs by preferentially forming conjugates with them. Uptake of DC IL-2 by Tregs required cell-cell contact and CD25. Tregs increased levels of CD25 and Foxp3 from baseline and showed greater suppressor function when co-cultured with IL-2-sufficient DCs, but not when co-cultured with IL-2(-/-) DCs. Exogenous IL-2, added in excess of 500 U/ml to co-cultures with IL-2(-/-) DCs, restored Treg suppressor function. These data support a model of juxtacrine delivery of IL-2 from DCs to Tregs and suggest that a subset of DCs modulates Treg function through controlled, spatial delivery of IL-2. Knowledge of how DCs regulate Tregs should be integrated into the design of interventions intended to alter Treg function.
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Affiliation(s)
- Katarina Kulhankova
- Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
| | - Todd Rouse
- Department of Veterans Affairs Medical Center, Iowa City, Iowa, United States of America
| | - Mohamed E. Nasr
- Department of Veterans Affairs Medical Center, Iowa City, Iowa, United States of America
| | - Elizabeth H. Field
- Department of Veterans Affairs Medical Center, Iowa City, Iowa, United States of America
- Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
- * E-mail:
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46
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He F, Balling R. The role of regulatory T cells in neurodegenerative diseases. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2012; 5:153-80. [PMID: 22899644 DOI: 10.1002/wsbm.1187] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
A sustained neuroinflammatory response is the hallmark of many neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and HIV-associated neurodegeneration. A specific subset of T cells, currently recognized as FOXP3(+) CD25(+) CD4(+) regulatory T cells (Tregs), are pivotal in suppressing autoimmunity and maintaining immune homeostasis by mediating self-tolerance at the periphery as shown in autoimmune diseases and cancers. A growing body of evidence shows that Tregs are not only important for maintaining immune balance at the periphery but also contribute to self-tolerance and immune privilege in the central nervous system. In this article, we first review the current status of knowledge concerning the development and the suppressive function of Tregs. We then discuss the evidence supporting a dysfunction of Tregs in several neurodegenerative diseases. Interestingly, a dysfunction of Tregs is mainly observed in the early stages of several neurodegenerative diseases, but not in their chronic stages, pointing to a causative role of inflammation in the pathogenesis of neurodegenerative diseases. Furthermore, we provide an overview of a number of molecules, such as hormones, neuropeptides, neurotransmitters, or ion channels, that affect the dysfunction of Tregs in neurodegenerative diseases. We also emphasize the effects of the intestinal microbiome on the induction and function of Tregs and the need to study the crosstalk between the enteric nervous system and Tregs in neurodegenerative diseases. Finally, we point out the need for a systems biology approach in the analysis of the enormous complexity regulating the function of Tregs and their potential role in neurodegenerative diseases.
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Affiliation(s)
- Feng He
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Luxembourg
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47
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Hartemann A, Bourron O. Interleukin-2 and type 1 diabetes: new therapeutic perspectives. DIABETES & METABOLISM 2012; 38:387-91. [PMID: 22771204 DOI: 10.1016/j.diabet.2012.05.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 05/22/2012] [Indexed: 11/25/2022]
Abstract
A new sort of CD4+T cells, so-called regulatory T cells (Tregs), has been described in 1996. Tregs are suggested to have an important function consisting in controlling autoimmune reactions. In humans, absence of Tregs induces the IPEX syndrome characterized by the presence of several autoimmune diseases. These cells depend on interleukin-2 (IL-2) for proliferating and controlling the T effector cells (Teff) reaction, but they do not have the capacity to produce IL-2. In type 1 diabetes (T1DM), a hypothesis is that a lack of IL-2 in pancreas could prevent Tregs action and lead to beta cells destruction. In NOD mice, low dose IL-2 treatment at the initial time of diabetes can rescue insulin secretion by restoring proteins expression that are necessary for Tregs regulatory function in the pancreas. Using low doses instead of high doses IL-2 prevents Teff activation which also depends on IL-2. These results led to conduct a dose-effect trial in human T1DM. This trial aimed at determining the therapeutic condition, which induces Tregs activation without major side effects, in a therapeutic perspective to recover insulin secretion at the apparition of diabetes.
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Affiliation(s)
- A Hartemann
- AP-HP, Pitié-Salpêtrière Hospital, Endocrinology, Nutrition and Diabetes Department, 83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
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48
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Pleiotropic targets: the problem of shared signaling circuitry in rheumatoid arthritis disease progression and protection. Future Med Chem 2012; 4:735-50. [PMID: 22530638 DOI: 10.4155/fmc.12.27] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The immune response is replete with feedback control at many levels. These protective circuits are even functional within the arthritic joint, tempering disease to varying extents. An optimal therapy would inhibit autoimmune processes while maintaining protective circuitry. However, many of the cells and proteins that serve as important mediators of disease progression also play an active role in these protective circuits. The hypothesis considered in this review is that the inadvertent inhibition of protective circuitry adversely affects efficacy. Conversely, if therapeutics can be designed, which avoid inhibiting known regulatory circuits, efficacy will be improved. Understanding where these processes share signaling molecules will be crucial to the development of the next generation of therapeutics. This review discusses three well-defined signal transduction cascades; IL-2, IFNγ and TNF-α, and demonstrate within two cell types, T cells and macrophages, how these cytokines may contribute both to protection and to disease progression.
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Li Q, Shakya A, Guo X, Zhang H, Tantin D, Jensen PE, Chen X. Constitutive nuclear localization of NFAT in Foxp3+ regulatory T cells independent of calcineurin activity. THE JOURNAL OF IMMUNOLOGY 2012; 188:4268-77. [PMID: 22490438 DOI: 10.4049/jimmunol.1102376] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Foxp3 plays an essential role in conferring suppressive functionality to CD4(+)/Foxp3(+) regulatory T cells (Tregs). Although studies showed that Foxp3 has to form cooperative complexes with NFAT to bind to target genes, it remains unclear whether NFAT is available in the nucleus of primary Tregs for Foxp3 access. It is generally believed that NFAT in resting cells resides in the cytoplasm, and its nuclear translocation depends on calcineurin (CN) activation. We report that a fraction of NFAT protein constitutively localizes in the nucleus of primary Tregs, where it selectively binds to Foxp3 target genes. Treating Tregs with CN inhibitor does not induce export of NFAT from the nucleus, indicating that its nuclear translocation is independent of CN activity. Consistently, Tregs are resistant to CN inhibitors in the presence of IL-2 and continue to proliferate in response to anti-CD3 stimulation, whereas proliferation of non-Tregs is abrogated by CN inhibitors. In addition, PMA, which activates other transcription factors required for T cell activation but not NFAT, selectively induces Treg proliferation in the absence of ionomycin. TCR interaction with self-MHC class II is not required for PMA-induced Treg proliferation. Tregs expanded by PMA or in the presence of CN inhibitors maintain Treg phenotype and functionality. These findings shed light on Treg biology, paving the way for strategies to selectively activate Tregs.
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Affiliation(s)
- Qiuxia Li
- Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
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50
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