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Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis
  1. Caroline Coquerelle (caroline_coquerelle{at}hotmail.com)
  1. Université Libre de Bruxelles, Belgium
    1. Guillaume Oldenhove (guillaum{at}niaid.nih.gov)
    1. Université Libre de Bruxelles, Belgium
      1. Valérie Acolty (valerie.acolty{at}ulb.ac.be)
      1. Université Libre de Bruxelles, Belgium
        1. Julie Denoeud
        1. Université Libre de Bruxelles, Belgium
          1. Georgette Vansanten (gvsanten{at}ulb.ac.be)
          1. Université Libre de Bruxelles, Belgium
            1. Jean-Marc Verdebout
            1. Institut de Pathologie et de Génétique, Belgium
              1. Andrew Mellor (amellor{at}mcg.edu)
              1. Medical College of Georgia, United States
                1. Jeffrey A Bluestone (jbluest{at}diabetes.ucsf.edu)
                1. UCSF Diabetes Center, United States
                  1. Muriel Moser (mmoser{at}ulb.ac.be)
                  1. Université Libre de Bruxelles, Belgium

                    Abstract

                    Background and aims: CTL-associated antigen 4 (CTLA-4) has been shown to act as a negative regulator of T cell function and has been implicated in the regulation of Th1/Th2 development and the function of regulatory T cells. We tested whether anti-CTLA-4 treatment would alter the polarization of naive T cells in vivo.

                    Methods: Mice were treated with anti-CTLA-4 mAb (UC10-4F10) at the time of immunization or colonic instillation of trinitrobenzene sulfonic acid (TNBS). We tested the cytokines produced by lymph node cells after in vitro antigenic stimulation, the role of indoleamine 2,3 dioxygenase (IDO) and of interleukin-10, and monitored the survival of mice.

                    Results: Injection of anti-CTLA-4 mAb in mice during priming induced the development of adaptive CD4+ regulatory T cells which expressed high levels of ICOS, secreted IL-4 and IL-10. This treatment inhibited Th1 memory responses in vivo and repressed experimental intestinal inflammation. The anti-CTLA-4-induced amelioration of disease correlated with IDO expression and infiltration of ICOShigh Foxp3+ T cells in the intestine, suggesting that anti-CTLA-4 acted indirectly through the development of regulatory T cells producing IL-10 and inducing IDO.

                    Conclusions: These observations emphasize the synergy between IL-10 and IDO as anti-inflammatory agents and highlight anti-CTLA-4 treatment as a potential novel immunotherapeutic approach for inducing adaptive regulatory T cells.

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