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T Cells Via IL-2 Production Δγ Human B7−CD28 Costimulatory Signals Control the Survival and Proliferation of Murine and Human δγ T Cells via IL-2 Production This information is current as Julie C. Ribot, Ana deBarros, Liliana Mancio-Silva, Ana of September 24, 2021. Pamplona and Bruno Silva-Santos J Immunol 2012; 189:1202-1208; Prepublished online 25 June 2012; doi: 10.4049/jimmunol.1200268 http://www.jimmunol.org/content/189/3/1202 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/06/25/jimmunol.120026 Material 8.DC1 http://www.jimmunol.org/ References This article cites 49 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/189/3/1202.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology B7–CD28 Costimulatory Signals Control the Survival and Proliferation of Murine and Human gd T Cells via IL-2 Production Julie C. Ribot,* Ana deBarros,* Liliana Mancio-Silva,*,† Ana Pamplona,* and Bruno Silva-Santos*,‡ gd T cells play key nonredundant roles in immunity to infections and tumors. Thus, it is critical to understand the molecular mechanisms responsible for gd T cell activation and expansion in vivo. In striking contrast to their ab counterparts, the costimulation requirements of gd T cells remain poorly understood. Having previously described a role for the TNFR superfamily member CD27, we since screened for other nonredundant costimulatory receptors in gd T cell activation. We report in this article that the Ig superfamily receptor CD28 (but not its related protein ICOS) is expressed on freshly isolated lymphoid gd T cells and Downloaded from synergizes with the TCR to induce autocrine IL-2 production that promotes gd cell survival and proliferation in both mice and humans. Specific gain-of-function and loss-of-function experiments demonstrated a nonredundant function for CD28 interactions with its B7 ligands, B7.1 (CD80) and B7.2 (CD86), both in vitro and in vivo. Thus, gd cell proliferation was significantly enhanced by CD28 receptor agonists but abrogated by B7 Ab-mediated blockade. Furthermore, gd cell expansion following Plasmodium infection was severely impaired in mice genetically deficient for CD28. This resulted in the failure to mount both IFN-g–mediated and IL-17–mediated gd cell responses, which contrasted with the selective effect of CD27 on IFN-g–producing gd cells. Our data http://www.jimmunol.org/ collectively show that CD28 signals are required for IL-2–mediated survival and proliferation of both CD27+ and CD272 gd T cell subsets, thus providing new mechanistic insight for their modulation in disease models. The Journal of Immunology, 2012, 189: 1202–1208. d T cells have been evolutionarily conserved as a lym- dendritic cells (DCs) or B cells (9). B7–CD28 signaling in ab g phocyte lineage whose signature TCR (TCRgd) does not T cells was shown to have both qualitative and quantitative effects obey the paradigm of MHC restriction (1). In fact, we that lower activation thresholds, promote cell proliferation, and know very little about Ag specificity and recognition via TCRgd enhance functional activity in vitro and in vivo (reviewed in Refs. by guest on September 24, 2021 (2). Although this has not precluded advances in exploiting the 9–11). functional properties of these lymphocytes, particularly in cancer In contrast to this well-established function in ab T cells, immunotherapy (3), or in dissecting their pathological contribu- theroleofCD28ingd T cell activation has remained contro- tion to autoimmunity (4–6), it remains a priority to understand versial because of discrepant results of previous studies (7). how gd cells are activated in vivo. As part of our efforts to elu- In particular, resting murine gd splenocytes (12) and various cidate the contribution of costimulatory receptors to this process intraepithelial lymphocytes subsets (13–15) were reported to be (7, 8), we addressed the role of the Ig superfamily protein CD28. devoid of CD28 expression, which was observed, however, upon Much of what we know about T cell costimulation has come cellular activation (12). This pattern contrasted with that of human from studies on CD28 and its ligands, B7.1 (CD80) and B7.2 Vd2+ PBLs, which significantly downregulated CD28 following (CD86), which are typically found on professional APCs, such as activation (16). Moreover, human Vd1+ cells, unlike their Vd2+ counterparts, failed to express CD28 (17). Furthermore, although *Unidade de Imunologia Molecular, Instituto de Medicina Molecular, Faculdade de CD28 signals promoted the in vitro proliferation of mouse Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; †Unidade de Mala´ria, splenocytes (12, 15) and human gd lymphocytes (18), the allor- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, eactivity of murine Vg2+ transgenic thymocytes was normal in the 1649-028 Lisboa, Portugal; and ‡Instituto Gulbenkian de Cieˆncia, 2781-901 Oeiras, Portugal absence of CD28 signaling (19). Critically, none of these studies Received for publication January 23, 2012. Accepted for publication May 24, 2012. examined the role of CD28 costimulation during physiological gd cell responses to infection. This work was supported by Fundac¸a˜o para a Cieˆncia e Tecnologia (PTDC/SAU-MII/ 104158/2008) and the European Molecular Biology Organization (Young Investiga- In this study, we used the last generation of specific mAbs and tor Programme). L.M.-S. is supported by a European Molecular Biology Organiza- genetically manipulated mice to unequivocally assess the impact of tion fellowship (ALTF960-2009). B7–CD28 signals in the context of gd cell responses to Plasmo- Address correspondence and reprint requests to Prof. Bruno Silva-Santos or Dr. Julie dium parasites, the infectious agents that cause malaria. Infection Ribot, Unidade de Imunologia Molecular, Instituto de Medicina Molecular, Avenida Prof. Egas Moniz, 1649-028 Lisboa, Portugal. E-mail addresses: [email protected] by Plasmodium is known to cause striking expansions of gd cells (B.S.-S.) and [email protected] (J.R.) both in mice (20–22) and in humans (23–26). In fact, in patients The online version of this article contains supplemental material. infected with either Plasmodium falciparum (23, 24) or Plasmo- Abbreviations used in this article: B6, C57BL/6; DC, dendritic cell; HMB-PP, 4- dium vivax (25), gd cells frequently expand to 30–40% of all hydroxy-3-methyl-but-2-enyl pyrophosphate; ICOSL, ICOS ligand; LN, lymph node; peripheral blood T cells (compared with 1–5% in healthy donors). OX40L, OX40 ligand; PbA, Plasmodium berghei ANKA; WT, wild-type. Moreover, gd cells were shown to be the major cellular source of Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 the key proinflammatory cytokine IFN-g in patients in endemic www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200268 The Journal of Immunology 1203 areas (27), and this correlated with reduced incidence of clinical were used as blocking reagents; anti-mouse mAbs for CD3ε (145.2C11) and episodes (28). Therefore, malaria constitutes one of the most CD28 (37.51) were used as agonists. relevant physiological contexts in which to investigate gd cell The following anti-human mAbs were used for flow cytometry: anti– CD28-FITC (CD28.2; eBioscience); anti–CD69-PE (FN50), anti–CD70- activation. We performed a comprehensive series of gain-of- PE (ki-24), anti–CD80-PE (L307.4), and anti–CD86-allophycocyanin function and loss-of-function studies that demonstrates a critical (2331) (all from BD Pharmingen, San Diego, CA); and anti–OX40 ligand role for B7–CD28 interactions in the activation and expansion of (OX40L)-PE (11C3.1) and anti–ICOS ligand (ICOSL)-PE (2D3) (both murine and human proinflammatory gd T cell subsets in response from BioLegend, San Diego, CA). The mAbs used as blocking reagents in human cell cultures were anti- to Plasmodium Ags. CD70 (ki-24) and anti-CD86 (IT2.2) (both from BD Pharmingen); anti- ICOSL (9F.8A4; BioLegend); and anti-CD80 (37711) and anti-OX40L Materials and Methods (159403) (both from R&D Systems). IgG1 (MOPC-21), IgG2 (MPC-11), Mice and IgG3 (MG3-35) were used as isotype controls (all purchased from BioLegend). All mice were adults 4–10 wk of age. C57BL/6 (B6), B6.TCRa-deficient (Tcra2/2), and B6.CD28-deficient (Cd282/2) mice were described previ- Flow cytometry and cell sorting ously (29, 30) and were obtained from The Jackson Laboratory. B6.CD27- 2/2 Cells were sorted electronically using a FACSAria (BD Biosciences, San deficient (Cd27 ) mice were a kind gift from Dr. Jannie Borst (Neth- Jose, CA). For cell surface stainings, cells were incubated for 15 min on ice erlands Cancer Institute, Amsterdam, The Netherlands). Mice were bred in 2.4G2 (anti-FcgR mAb) hybridoma supernatant and then incubated for and maintained in the specific pathogen-free animal facilities of Instituto 6 15 min with saturating concentrations of the indicated mAbs. For intra- de Medicina Molecular. When stated, mice were infected i.p. with 10 cellular cytokine staining, cells were stimulated with PMA (50 ng/ml) and Plasmodium berghei ANKA (PbA)-infected erythrocytes and monitored as ionomycin (1 mg/ml) (both from Sigma) for 4 h at 37˚C; 10 mg/ml bre- Downloaded from described (31).
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