Osteopontin Production Crucial Role in Lupus Pathogenesis Via with Cell
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A CD153+CD4+ T Follicular Cell Population with Cell-Senescence Features Plays a Crucial Role in Lupus Pathogenesis via Osteopontin Production This information is current as of September 30, 2021. Suhail Tahir, Yuji Fukushima, Keiko Sakamoto, Kyosuke Sato, Harumi Fujita, Joe Inoue, Toshimitsu Uede, Yoko Hamazaki, Masakazu Hattori and Nagahiro Minato J Immunol 2015; 194:5725-5735; Prepublished online 13 May 2015; Downloaded from doi: 10.4049/jimmunol.1500319 http://www.jimmunol.org/content/194/12/5725 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/05/13/jimmunol.150031 Material 9.DCSupplemental References This article cites 41 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/194/12/5725.full#ref-list-1 Why The JI? Submit online. by guest on September 30, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! 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The Journal of Immunology A CD153+CD4+ T Follicular Cell Population with Cell-Senescence Features Plays a Crucial Role in Lupus Pathogenesis via Osteopontin Production Suhail Tahir,* Yuji Fukushima,† Keiko Sakamoto,* Kyosuke Sato,* Harumi Fujita,* Joe Inoue,* Toshimitsu Uede,‡ Yoko Hamazaki,* Masakazu Hattori,† and Nagahiro Minato* Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD- 1+ CD44highCD4+ T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1+ CD44highCD4+ T cells develop as unique T follicular (TF) cells in a B cell–dependent manner and consist of two subpopulations, as follows: CD153+ cells preferentially secreting abundant osteopontin on TCR stimulation and CD1532 cells that are apparently Downloaded from TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the sponta- neous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4+ T cell proliferation in vivo, suggesting replicative senescence. Although the CD153+ TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor–induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153+ PD-1+ CD4+ T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC http://www.jimmunol.org/ enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153+ TF cells generated as a consequence of extensive endogenous CD4+ T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmu- nity risk with age. The Journal of Immunology, 2015, 194: 5725–5735. erminal centers (GCs) are unique niches in secondary may be recruited to GCs, including TF helper (TFH) cells, regu- lymphoid tissues in which a specific Ab response occurs latory T cells, and NKT cells (7). G after Ag immunization (1). In GCs, Ag-specific B cells GC reactions may occur spontaneously in various autoimmune by guest on September 30, 2021 undergo a series of dynamic processes, including robust prolifer- diseases, including lupus (8, 9). Lupus disease, which preferen- ation, somatic hypermutation, and class-switch recombination of tially affects young females in humans, is a multifactorial disease BCR genes, affinity maturation, and differentiation into memory affecting various organs, most commonly glomerulonephritis. A or plasma cells (2). The initiation of GC reaction requires Ag- hallmark of the disease is production of autoantibodies against specific T cells (3). After Ag immunization, some of these T cells a diverse spectrum of self-Ags, including nuclear components (10, migrate into the follicular B cell region to regulate specific GC 11). Among several immune disorders in lupus is a defective reactions and are called T follicular (TF) cells (4–6). Accumu- checkpoint of B cell self-tolerance (12). Although potentially self- lating evidence indicates that functionally distinct types of T cells reactive B cells are normally excluded from GCs, they are in- cluded in GCs in the lupus-prone genetic background, leading to overt autoantibody production (13, 14). Recent studies highlight *Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto an important role of TF cells in the spontaneous GC reactions of University, Kyoto 606-8501, Japan; †Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, lupus disease (15–17). However, it remains elusive how such spon- Kyoto 606-8501, Japan; and ‡Division of Molecular Immunology, Institute for Ge- taneous GC reactions develop and are regulated. netic Medicine, Hokkaido University, Sapporo 060-0815, Japan We previously identified a PD-1+ CD44highCD62LlowCD4+ Received for publication February 10, 2015. Accepted for publication April 17, 2015. T cell population that steadily increases age dependently in normal This work was supported by a Grant-in-Aid for Scientific Research on Innovative B6 mice (18). The CD4+ T cell population, termed senescence- Areas from the Japan Society for the Promotion of Science; Special Coordination associated T (SA-T) cells, shows unique genetic signature and Funds for Promoting Science and Technology from the Japanese Government; the “Formation of Innovation Center for Fusion of Advanced Technologies” program of functional features, including attenuated TCR-mediated prolifer- Astellas Pharma, Inc.; the Uehara Memorial Foundation; and Ono Pharmaceutical ation and highly biased secretion of osteopontin (OPN), suggest- Co., Ltd. ing their contribution to reduced acquired immunity and increased Address correspondence and reprint requests to Prof. Nagahiro Minato, Department inflammatory trait in senescence (18). Most recently, it was re- of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. E-mail address: [email protected] ported that unique TF cells with a similar genetic signature to SA- The online version of this article contains supplemental material. T cells were increased in B6.Sle1b congenic mice (19), which Abbreviations used in this article: ANA, anti-nuclear Ab; EGFP, enhanced GFP; develop anti-nuclear Abs (ANAs) but no clinical disease (11). f-BWF1, female BWF1; GC, germinal center; miR, microRNA; OPN, osteopontin; Although Slamf6 receptor coded in a Sle1b gene cluster was in- PNA, peanut agglutinin; SA-T, senescence-associated T; TF, T follicular; TFH, TF dicated to play a crucial role in the increase of TF cells and ANA helper. production (19), the origin and relation of them with SA-T cells Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 remain unknown. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500319 5726 SENESCENT CD153+ TF CELLS IN LUPUS PATHOGENESIS In the current study, we indicate that SA-T cells develop as a unique Laser-capture microdissection TF cell population in normal B6 mice with age and much prematurely Cryostat sections were affixed to frame membrane slides for the ArcturusXT in bone fide lupus-prone female BWF1 (f-BWF1) mice, in association LMD system (Life Technologies), fixed in acetone, and stained with bio- with spontaneous GC reactions. The SA-T cells in both aged B6 mice tinylated PNA and HistoGene immunofluorescence staining kit. After XT andf-BWF1micearedevelopedinassociation with extensive en- dehydration, the regions of interest were dissected on an Arcturus sys- dogenous CD4+ T cell proliferation in vivo and show characteristic tem (Life Technologies). cell-senescence features. We demonstrate that a minor cell population Quantitative PCR expressing CD153 in the SA-T cells plays a crucial role in sponta- Quantitative PCR was performed with SYBR Green I Master mix (Roche) on neous GC reactions and development of clinical lupus nephritis. a LightCycler 480 (Roche). Cyclophilin and U6 RNA were used as internal controls for mRNA and microRNAs (miRs), respectively. Primer sequences Materials and Methods for genes and miR are as follows: Tnfsf8,59-GAGGATCTCTTCTG- TACCCTGAAA-39 and 59-TTGGTATTGTTGAGATGCTTTGA-39; Spp1, Mice 59-CCCGGTGAAAGTGACTGATT-39 and 59-TTCTTCAGAGGACACA- New Zealand White, New Zealand Black, New Zealand Black 3 New GCATTC-39; Il1r2,59-CCCATCCCTGTGATCATTTC-39 and 59-GCAC- GGGACTATCAGTCTTGA-39; Ccl3,59-TCTGTCACCTGCTCAACA- Zealand White F1 (BWF1), and C57BL/6 (B6) mice were purchased from Japan SLC, and mMT mice were provided by M. Reth