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Cells Through Regulation of Follicular Helper T B7RP-1 Blockade

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Cells Through Regulation of Follicular Helper T B7RP-1 Blockade The Journal of Immunology B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells Yi-Ling Hu,* Daniela P. Metz,* James Chung,† Gerald Siu,1 and Ming Zhang2* Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Co- stimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (TFH cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of TFH cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F1 mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in TFH cells and GC B cells as well as an overall decrease in the frequency of ICOS؉ T cells. Coculture experiments of Ag-primed B cells with CXCR5؉ or CXCR5؊ T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the TFH cell pool is an important mechanism by which ICOS regulates Ab production. The Journal of Immunology, 2009, 182: 1421–1428. ffective activation of T cells via their Ag receptor requires ing anti-B7RP-1 reagents effectively inhibited the initiation and additional stimuli provided by cell-surface costimulatory maturation of an Ab-mediated Ag response (15). In addition, E molecules (1, 2). The prototypical costimulatory receptor ICOS/B7RP-1 blockade has been shown to be efficacious in CD28 is expressed constitutively on T cells, and its interaction mouse models of lupus nephritis (16), rheumatoid arthritis (17), with the ligands CD80 and CD86 was determined to be critical for and myasthenia gravis (18). the activation of naive T cells (1, 2). Subsequently, a second mol- The maturation of the Ag-specific B cell response occurs within ecule was identified, referred to as ICOS, which was closely re- specific structures within the secondary lymph organs. The forma- lated structurally to CD28 (3–6). Initial experiments indicated that tion of these structures, referred to as GCs, is the anatomic hall- the interaction of ICOS with its ligand B7RP-1, like the CD28/ mark of TH cell activity during a T cell-dependent B cell immune CD80-CD86 interactions, is critical for a wide variety of T cell response (19). During the initiation of the immune response, den- responses (1–9). In vitro experiments demonstrated that both dritic cells present Ag to TH cells, which in turn induce cognate B by guest on October 1, 2021. Copyright 2009 Pageant Media Ltd. CD28 and ICOS effectively enhance all basic T cell responses, cells to proliferate. As the response matures, the proliferating B including proliferation, up-regulation of molecules mediating cell- cells form the germinal center within a B cell-rich region referred cell interaction, synthesis of cytokines, and B cell help for Ab to as the follicle, where ongoing somatic hypermutation and Ig secretion (10, 11). Although CD28 and ICOS induce the secretion class switching occurs (19, 20). These B cells compete for TH of an overlapping spectrum of T cell cytokines, only CD28 elicits support from T cells adjacent to the follicle (21, 22); B cells ex- abundant IL-2 generation, whereas ICOS is particularly effective pressing immunoglobulins with mutations that improve the affinity in inducing IL-10 release, a cytokine implicated in the gener- for Ag either return to the GC for additional rounds of mutation or ation of B cell memory and plasma cells (11). B7RP-1 and migrate to the periphery, whereas B cells that obtain mutations that ICOS-deficient mice as well as ICOS null patients showed sim- render the Ig autoreactive are deleted (20). The T cells on the http://classic.jimmunol.org ilar phenotypes of defective T cell-dependent Ab response, Ig margin of the follicle are specialized for B cell help and are re- 3 class switching and germinal center (GC) formation (12–14); ferred to as follicular Th (TFH) cells (20). These cells express high pharmacological blockade of the ICOS/B7RP-1 interaction us- constitutive levels of ICOS, further suggesting an important role for the ICOS/B7RP-1 pathway in the B cell mediated immune response (20–22). *Department of Inflammation and †Department of Medical Sciences, Amgen, Inc., Thousand Oaks, CA 91320 We speculated that the ICOS/B7RP-1 interaction might be play- Downloaded from ing a critical role in the induction of disease by enhancing the Received for publication June 24, 2008. Accepted for publication November 23, 2008. development and/or function of autoimmune TFH cells, leading to The costs of publication of this article were defrayed in part by the payment of page the development of autoimmune GC B cells and the production of charges. This article must therefore be hereby marked advertisement in accordance autoimmune Abs. To address this issue, we studied the role of TFH with 18 U.S.C. Section 1734 solely to indicate this fact. and the ICOS/B7RP-1 pathway in murine models of B cell-medi- 1 Current address: Immunoinflammation Centre of Excellence for Drug Discovery, ated autoimmune disease using pharmacological blockade. We GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY U.K. demonstrate that blockade of the ICOS/B7RP-1 pathway with a 2 Address correspondence and reprint requests to Dr. M. Zhang, Amgen Inc., M/S B29-2-C, Amgen Centre Drive, Thousand Oaks, CA 91320. E-mail address: mAb against B7RP-1 leads both to reduction of TFH and GC B cell [email protected] number as well as to amelioration of disease manifestations in 3 Abbreviations used in this paper: GC, germinal center; TFH cell, follicular T helper cell; murine models of rheumatoid arthritis and systemic lupus ery- CIA, collagen-induced arthritis; CII, collagen II; NZB/NZW, New Zealand Black/New thematosus (SLE). Although purified T cells are capable of in- Zealand White; PNA, peanut agglutinin; SLE, systemic lupus erythematosus. FH ducing Ig production from GC B cells in in vitro culture, ICOS/ Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 B7RP-1 blockade does not inhibit this process. These data indicate www.jimmunol.org 1422 B7RP-1 REGULATES TFH CELLS IN AUTOIMMUNITY that the ICOS/B7RP-1 pathway is critical for B cell-mediated sciences unless otherwise indicated. Flow cytometry was performed with a pathogenic autoimmune processes by affecting development but FACSCalibur (BD Biosciences), and the data were analyzed using the FlowJo program (Tree Star). not the function of TFH cells, and that the blockade of this pathway may therefore be beneficial in the prevention and treatment of ELISAs these diseases. Anti-CII Ab ELISA. Serum samples were collected on day 14 and 34 from CII-immunized DBA/1J mice and anti-CII Ab level was measured by Materials and Methods ELISA. In brief, plates coated with bovine CII (Chondrex) were incubated Mice for2hatroom temperature with serial dilutions of serum samples obtained from the test mice. Bound CII-specific Ig was detected with HRP-conju- Specific pathogen-free 8-wk-old male DBA/1J mice and female New Zea- gated goat anti-mouse IgG1, IgG2a, and IgG2b Abs (Southern Biotech- land Black/New Zealand White (NZB/NZW) F1 mice were purchased from nology Associates). The substrate reaction was performed with Sureblue The Jackson Laboratories. Specific pathogen-free 6- to 8-wk-old female TMB microwell peroxidase substrate (Kirkegaard & Perry Laboratories) BALB/c mice were purchased from Charles River Laboratories. Mice were and the OD was read using Spectrum Max (Molecular Devices). A standard housed under pathogen-free conditions at the Laboratory Animal Research serum composed of a mixture of sera from arthritic mice was added to each Facility at Amgen. Animal experiments were conducted as approved by plate in serial dilutions and a standard curve was constructed. Institutional Animal Care and Use Committee of Amgen. Anti-dsDNA Ab ELISA. Serum anti-dsDNA IgG level in NZB/NZW F1 mice was measured by ELISA using a mouse anti-dsDNA ELISA kit (Al- Antibody reagents and the induction and assessment of pha Diagnostic) following the manufacturer’s instructions. collagen-induced arthritis Anti-SRBC Ab ELISA. In brief, plates coated with 10 ␮g/ml soluble SRBC The generation of the chimeric mouse anti-mouse B7RP-1 mAb clone Ag were incubated for2hatroom temperature with diluted cell culture 1B7-V2 as well as the rat anti-mouse B7RP-1 mAb 18A5 was described supernatant. Bound SRBC-specific Ig was detected with HRP-conjugated previously. Mouse IgG1 isotype control was supplied by Amgen. Col- goat anti-mice IgG and IgM Abs (Southern Biotechnology Associates). lagen-induced arthritis (CIA) was induced as described earlier (24). In The substrate reaction was performed with Sureblue TMB microwell per- brief, male DBA/1J mice (7- to 10-wk-old) were injected intradermally at oxidase substrate (Kirkegaard & Perry Laboratories) and the OD was read the base of the tail with 200 ␮g of bovine collagen II (CII) (Chondrex) using Spectrum Max (Molecular Devices). A standard serum composed of emulsified in CFA (Difco Laboratories). Twenty-one days after primary a mixture of sera from SRBC immunized mice was added to each plate in immunization, the mice were boosted in the same way. The day of the serial dilutions and a standard curve was constructed.
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