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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. C Coquerelle1,
  2. G Oldenhove1,
  3. V Acolty1,
  4. J Denoeud1,
  5. G Vansanten1,
  6. J-M Verdebout2,
  7. A Mellor3,
  8. J A Bluestone4,
  9. M Moser1
  1. 1
    Département de Biologie Moléculaire, Université Libre de Bruxelles, Gosselies, Belgium
  2. 2
    Département d’anatomopathologie, Institut de Pathologie et de Génétique, Gosselies, Belgium
  3. 3
    Immunotherapy Center, Medical College of Georgia, Augusta, Georgia, USA
  4. 4
    UCSF Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA
  1. Correspondence to Dr M Moser, Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Rue des Pr Jeener et Brachet, 12, 6041 Gosselies, Belgium; mmoser{at}ulb.ac.be

Abstract

Background and aims: Cytotoxic T lymphocyte-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 T helper 1 (Th1)/Th2 development and the function of regulatory T cells. Tests were carried out to determine whether anti-CTLA-4 treatment would alter the polarisation of naive T cells in vivo.

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

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 (inducible co-stimulator), 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 emphasise 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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Footnotes

  • Funding The Laboratory of Animal Physiology is supported by grants of the Fonds National de la Recherche Scientifique (FNRS)/Télévie, by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, by the Programme of Excellence (CIBLES) initiated by the Walloon Region, by European Grants (DC-THERA, Cancerimmunotherapy) and by the Belgian Cancer Foundation. CC and GO have fellowships from the FNRS; MM is Research Director from the FNRS.

  • Competing interests Declared (the declaration can be viewed on the Gut website at http://www.gut.bmj.com/supplemental).

  • Provenance and Peer review Not commissioned; externally peer reviewed.

  • ▸ Additional methods and figures are published online only at http://gut.bmj.com/content/vol58/issue10

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