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IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF−Producing Δγ T Cells in the Muscle

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IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF−Producing Δγ T Cells in the Muscle IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF−Producing δγ T Cells in the Muscle Takahiro Kageyama, Akira Suto, Taro Iwamoto, Shigeru Tanaka, Kenichi Suehiro, Yusuke Downloaded from Yokoyama, Aiko Saku, Shunsuke Furuta, Kei Ikeda, Kotaro Suzuki, Koichi Hirose and Hiroshi Nakajima ImmunoHorizons 2017, 1 (8) 176-187 doi: https://doi.org/10.4049/immunohorizons.1700053 http://www.immunohorizons.org/content/1/8/176 http://www.immunohorizons.org/ This information is current as of September 26, 2021. Supplementary http://www.immunohorizons.org/content/suppl/2017/10/27/1.8.176.DCSupp Material lemental References This article cites 52 articles, 13 of which you can access for free at: http://www.immunohorizons.org/content/1/8/176.full#ref-list-1 by guest on September 26, 2021 Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://www.immunohorizons.org/alerts ImmunoHorizons is an open access journal published by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. ISSN 2573-7732. RESEARCH ARTICLE Adaptive Immunity IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF–Producing gd T Cells in the Muscle Takahiro Kageyama,*,1 Akira Suto,*,†,1 Taro Iwamoto,* Shigeru Tanaka,* Kenichi Suehiro,* Yusuke Yokoyama,* Aiko Saku,* Shunsuke Furuta,* Kei Ikeda,* Kotaro Suzuki,* Koichi Hirose,* and Hiroshi Nakajima* *Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; and †Institute for Global Downloaded from Prominent Research, Chiba University, Chiba 260-8670, Japan ABSTRACT http://www.immunohorizons.org/ IL-21 is suggested to be involved in the development of some autoimmune diseases; however, the role of IL-21 in autoimmune inflammatory myopathies (IMs) remains unknown. In this study, we found that serum levels of IL-21 were significantly elevated in a subset of IM patients. Upon the induction of experimental autoimmune myositis (EAM), IL-21 was produced by CD4+ T cells in the muscle, and muscle weakness and muscle inflammation were less obvious in IL-21–deficient (IL-212/2) mice compared with those in wild-type (WT) mice. Analysis of inflammatory cytokine production from draining lymph node cells of EAM-induced mice revealed that GM-CSF production was significantly decreased in IL-212/2 mice. Importantly, GM-CSF production from gdT cells, but not CD4+ T cells, was significantly reduced in EAM-induced IL-212/2 mice. In addition, the severity of EAM was attenuated by GM-CSF neutralization in WT mice or gdT cell deficiency. The majority of muscle-infiltrating GM-CSF–producing gdT cells expressed Vg4+Vd4+ TCR, and the number of Vg4+Vd4+ cells in the muscle was significantly decreased in EAM-induced IL-212/2 mice as compared with that in EAM-induced WT mice. Moreover, muscle-infiltrating Vg4+Vd4+ cells exhibited CX3CR1high phenotype, and the induction of by guest on September 26, 2021 Cx3cl1, a ligand for CX3CR1, in the muscle was reduced in EAM-induced IL-212/2 mice. Furthermore, reporter assays revealed that IL-21 activated the promoter of Cx3cl1. Consistent with these findings, serum levels of CX3CL1 were correlated with the levels of IL-21 in IM patients. Taken together, these results suggest that IL-21 facilitates autoimmune myositis through the accumulation of GM-CSF–producing Vg4+Vd4+ cells in the muscle possibly via CX3CR1-CX3CL1 pathways. ImmunoHorizons, 2017, 1: 176–187. INTRODUCTION of IL-23 and produce IL-17A, IL-17F, IL-21, and GM-CSF (1, 2). IL- 17–producing gdT cells are also activated by IL-23 and implicated Autoimmune diseases are caused by a breakdown of tolerance to in the pathogenesis of autoimmune diseases (3, 4). Because the self-antigens and are characterized by the activation of T cells, blocking of IL-17 signaling is less effective than that of IL-23 in including pathogenic IL-17–producing Th cells (Th17 cells). autoimmune disease models such as experimental autoimmune Pathogenic Th17 cells are eventually differentiated in the presence encephalomyelitis (EAE) (5, 6), Th17 cell–related cytokines other Received for publication October 3, 2017. Accepted for publication October 9, 2017. Address correspondence and reprint requests to: Dr. Akira Suto and Dr. Hiroshi Nakajima, Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan. E-mail addresses: [email protected] (A. Suto) and [email protected] (H.N.) ORCID: 0000-0002-2593-565X (A. Suto). 1T.K. and A. Suto contributed equally to this work. This work was supported by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government, the Leading Graduate School Program at Chiba University, and the Institute for Global Prominent Research, Chiba University, Japan. Abbreviations used in this article: CADM, clinically amyopathic DM; DM, dermatomyositis; EAE, experimental autoimmune encephalomyelitis; EAM, experimental autoimmune myositis; GC, germinal center; gf, gram-force; IL-212/2, IL-21–deficient; IL-21R2/2, IL-21R–deficient; IM, inflammatory myopathy; LN, lymph node; Mac, macrophage; PD-1, programmed death-1; PM, polymyositis; qPCR, quantitative PCR; RORgt, retinoid-related orphan receptor g t; SLEC, short-lived effector CD8+ T cell; TCRd2/2, TCRd-deficient; Tfh, follicular B Th; WT, wild-type. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license. Copyright © 2017 The Authors 176 https://doi.org/10.4049/immunohorizons.1700053 ImmunoHorizons is published by The American Association of Immunologists, Inc. ImmunoHorizons IL-21–Vg4+Vd4+ CELL AXIS IN AUTOIMMUNE MYOSITIS 177 than IL-17 seem to be important for the development of certain malignancy were excluded. We retrospectively assessed the autoimmune diseases. baseline patient characteristics, including age, sex, diagnosis, In the initiation phase of EAE, GM-CSF, a representative and presence of malignancy. The study was approved by the cytokine that induces the differentiation of neutrophils and Ethics Committees of Chiba University and was performed in macrophages (Macs), is produced by Th17 cells and serves a accordance with the principles expressed in the Declaration of nonredundant function (1, 2). In addition, it has been shown that Helsinki. IL-7–induced Stat5 activation promotes the development of GM- CSF–producing CD4+ T cells and causes severe EAE (7). More- ELISA over, GM-CSF is shown to be produced by gdT cells during the Serum levels of IL-21 and GM-GSF were analyzed by a human development of EAE (8). In humans, blocking of GM-CSF IL-21 ELISA MAX kit and a human GM-GSF ELISA MAX kit, signaling by a neutralizing Ab has shown promising results for respectively (BioLegend, San Diego, CA). Serum levels of human rheumatoid arthritis in early-phase clinical trials (9). These CX3CL1 and murine IL-21 were analyzed by a human CX3CL1/ findings suggest that GM-CSF is involved in the development of Fractalkine Quantikine ELISA Kit and a mouse IL-21 DuoSet some autoimmune diseases. ELISA, respectively (R&D Systems, Minneapolis, MN). Detection Recent studies have shown that IL-21 exhibits pleiotropic limits are as follows: human IL-21 .31.3 pg/ml, human GM-CSF Downloaded from effects on a variety of immune responses (10). IL-21 is produced by .7.8 pg/ml, human CX3CL1 .0.63 ng/ml, and murine IL-21 many types of CD4+ T cells such as Th17 cells (11), follicular B Th .62.5 pg/ml. (Tfh) cells (12, 13), IL-6– or IL-21–stimulated CD4+ T cells (14), CCR9+ Th cells (15), and “peripheral Th” cells (16). In addition, Mice IL-21 has been shown to be involved in the development of C57BL/6 mice were purchased from Charles River Laboratories http://www.immunohorizons.org/ autoimmune disease models, including type 1 diabetes in NOD (Atsugi, Kanagawa, Japan). IL-21–deficient (IL-212/2)mice mice (17), murine models of rheumatoid arthritis (18), and lupus (B6.129S-Il21tm1Lex/Mmucd) were obtained from Mutant Mouse (19, 20). Moreover, we have shown that IL-21–producing CD4+ Resource Research Centers. IL-21R–deficient (IL-21R2/2)mice T cells are increased in Foxp3 mutant scurfy mice, and that (27) were backcrossed over eight generations onto C57BL/6 mice. abrogation of IL-21 signaling in scurfy mice significantly prolongs TCRd-deficient (TCRd2/2) mice were obtained from the Jackson survival presumably by reducing autoimmune inflammation of Laboratory (Bar Harbor, ME). All mice were housed in micro- lung through the suppression of short-lived effector CD8+ T cells isolator cages under specific pathogen-free conditions. The Chiba (SLECs) (21). University Animal Care and Use Committee approved animal Polymyositis (PM) and dermatomyositis (DM) are the major procedures used in this study. subgroups of idiopathic inflammatory myopathy (IM), which is by guest on September 26, 2021 characterized by infiltration of inflammatory cells into the affected Experimental autoimmune myositis muscle (22, 23). Regarding the relationship between IL-21 and IM Experimental autoimmune myositis (EAM) was induced as in humans, it has been reported that CXCR32 CXCR5+ Th cells, described previously (28, 29). In brief, myosin was purified which are known to produce IL-21, are increased in peripheral from the muscle of C57BL/6 mice and emulsified with CFA with blood in juvenile DM patients who have skin rash and muscular 2mg/mlMycobacterium tuberculosis (CFA) (Chondrex, Redmond, weakness (24). However, the role of IL-21 in the pathogenesis of WA). Mice were immunized three times at 1-wk intervals with IM remains unknown. 1 mg of myosin in CFA on bilateral sides of hind foot pads (day 0), In this study, we addressed this issue by using a murine model tail base (day 7), and flanks (day 14) as described previously (29).
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