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ICOS Signaling Controls Induction and Maintenance of Collagen ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis Vincent Panneton, Sahar Bagherzadeh Yazdchi, Mariko Witalis, Jinsam Chang and Woong-Kyung Suh This information is current as of September 29, 2021. J Immunol published online 26 March 2018 http://www.jimmunol.org/content/early/2018/03/24/jimmun ol.1701305 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/03/24/jimmunol.170130 Material 5.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 26, 2018, doi:10.4049/jimmunol.1701305 The Journal of Immunology ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis Vincent Panneton,*,† Sahar Bagherzadeh Yazdchi,*,‡ Mariko Witalis,*,x Jinsam Chang,*,x and Woong-Kyung Suh*,†,‡,x ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr181-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr181-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule Downloaded from inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and main- tenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis. The Journal of Immunology, 2018, 200: 000–000. heumatoid arthritis (RA) is a chronic autoimmune disease synovial tissues, suggesting potential therapeutic value of ICOS- http://www.jimmunol.org/ characterized by immune cell infiltration of the synovial mediated T cell costimulatory pathways (9). R tissues leading to inflammation with potential destruction ICOS is a member of the CD28 superfamily mainly expressed at of cartilage and bone. The pathology of RA involves components of the surface of activated T cells (10, 11). The major role of ICOS is innate and adaptive immunity (1). Although the pathogenesis of to support differentiation and function of CD4+ follicular helper RA remains poorly understood, production of autoantibodies T (Tfh) cells during germinal center (GC) reactions (12–15). along with infiltration of synovial fluid and tissues by inflamma- Consequently, lack of ICOS or ICOSL in humans and mice causes tory cells have been identified as key events (2–4). Collagen- severe defects in class-switched Ab production (16–20). Alterna- induced arthritis (CIA) is a murine model that closely mimics tively, ICOS overexpression caused by the sanroque mutation RA (5). Susceptible mouse strains such as DBA/1 develop hu- leads to a lupus-like disease with an increase of Tfh cells and by guest on September 29, 2021 moral and cellular immune reactions to bovine type II collagen spontaneous GC reactions in mice (21, 22). Additionally, ICOS (bCII) following immunization, which leads to chronic joint in- signaling plays important roles in the production of an array of flammation (6). Studies have shown that T cell costimulation is Th1, Th2, and Th17 inflammatory cytokines depending on the involved in CIA. For example, mice deficient in CD28 are resis- context of immune stimuli (23–26). tant to CIA and blockade of ICOS using an mAb-ameliorated CIA Despite evidence suggesting that ICOS could be implicated in CIA (7, 8). Interestingly, RA patients were shown to have elevated and RA, little is known about the specific downstream signaling + levels of ICOS T cells along with ICOS ligand (ICOSL) in their components involved. We have previously described an evolutionarily conserved SH2 binding motif (Y181MFM) in the cytoplasmic tail of ICOS that is critical for the activation of the PI3K–Akt–mTOR signaling cascade (27, 28). Thus, mice carrying the ICOSY181F *Institut de Recherches Cliniques de Montre´al, Montreal, Quebec H2W 1R7, Canada; mutation cannot signal through this pathway and display reduced †Department of Microbiology, Infectiology, and Immunology, University of Montreal, Montreal, Quebec H3C 3J7, Canada; ‡Department of Microbiology and Immunology, numbers of Tfh cells and impaired GC reactions (27). However, x McGill University, Montreal, Quebec H3A 2B4, Canada; and Molecular Biology the ICOSY181F mutation does not completely phenocopy ICOS Program, University of Montreal, Montreal, Quebec H1T 2M4, Canada deficiency. For example, the anti-chlamydial Th17 response and ORCIDs: 0000-0001-7621-8178 (V.P.); 0000-0002-6420-3283 (W.-K.S.). graft-versus-host disease severity were only partially reduced in Received for publication September 12, 2017. Accepted for publication March 2, Y181F 2/2 2018. ICOS mice compared with ICOS mice (26, 29). These findings suggest the existence of PI3K-independent signaling mech- This work was supported by Canadian Institutes of Health Research Grant CIHR- 84544 (to W.-K.S.). V.P. is a recipient of a doctoral training award from Fonds de anisms of ICOS. In fact, there are two more signaling motifs iden- Recherche Sante´ Que´bec. tified in the cytoplasmic tail of ICOS. The second motif, KKKY170, Address correspondence and reprint requests to Dr. Woong-Kyung Suh, Institut de in the cytoplasmic tail of ICOS can potentiate intracellular calcium Recherches Cliniques de Montreal, 110 avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada. E-mail address: [email protected] release from the endoplasmic reticulum triggered by TCR engage- The online version of this article contains supplemental material. ment (30). The third TNFR-associated factor–like IProx motif links Abbreviations used in this article: bCII, bovine type II collagen; 3-BrPA, 3-bromopyr- ICOS to TANK-binding kinase 1 and serves as an important mech- uvate; CIA, collagen-induced arthritis; cKO, conditional KO; dLN, draining lymph anism promoting the late stage of Tfh cell differentiation (31). node; ES, embryonic stem; GC, germinal center; ICOSL, ICOS ligand; KO, knockout; However, its downstream signaling mechanisms remain unclear. Neo, neomycin resistance; RA, rheumatoid arthritis; Tfh, follicular helper T. In this study, we evaluated the impact of ICOS signaling on CIA Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 initiation and maintenance using ICOS mutant mice. We found www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701305 2 ROLE OF ICOS SIGNALING IN CIA INITIATION AND MAINTENANCE that ICOS is required for both induction and maintenance of Proliferation assay and cytokine ELISA CIA. Although these two processes are heavily dependent on 181 Cells were isolated by mechanical disruption from draining lymph nodes Tyr -mediated ICOS signaling, the downstream effector path- (dLN) of immunized mice and resuspended at 1 3 106/ml in RPMI 1640 ways are distinct. Importantly, we uncovered a potential overlap medium (Life Technologies) supplemented with 10% FBS (Wisent), between ICOS signaling, T cell glycolysis, and joint inflammation. 10 mM HEPES (Thermo Fisher), 100 U/ml penicillin-streptomycin (Thermo Fisher), and 55 mM 2-ME (Thermo Fisher). Cells were restimulated with 100 mg/ml heat-denatured bCII (Chondrex) or 1 mg/ml anti-CD3 (clone 145-2C11; Bio X Cell) for 2 d at 37˚C in 96-well plates Materials and Methods (1 3 105 per well). Cytokine concentrations in culture supernatant were Mice measured using cytokine Ready-SET-Go! ELISA kits (Thermo Fisher) Y181F according to the manufacturer’s instructions. For proliferation assays, cells ICOS germline knockout and ICOS knockin mice have been pre- were pulsed with 1 mCi per well [3H]thymidine (PerkinElmer) for 8 h at viously described (17, 27). For CIA experiments, these two lines have 37˚C, lysed, and harvested using a FilterMate harvester (Packard) and then been backcrossed onto DBA/1J background for 12 generations. DBA/1J analyzed using a TopCount NXT scintillation counter (Packard). mice (Jax 000670), UBC-CreERT2 mice (Jax 008085), and the FLPe FRT deleter line (Jax 005703) were purchased from The Jackson Lab- Glucose metabolism assay oratory. All mice were housed in the Institut de Recherches
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