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* INSERM, Paris, France;
Université Paris Descartes, Faculté de Médecine, Paris, France;
Laboratoire d’Immunologie Clinique, Institut Pasteur de Tunis, Tunisia; and
University of Groningen, University Medical Center Groningen, Department of Pediatrics, The Netherlands
IL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-β through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-β and CD4+ regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-β on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-β, IL-15 enhanced the acquisition of regulatory functions by CD4+CD25– T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-
production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of IL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from INSERM, Fondation Princesse Grace, Association pour la Recherche Contre le Cancer, Ligue Contre le Cancer, Agence Nationale pour La Recherche, Fondation pour la Recherche Médicale-Equipes 2007, and Association Française des Intolérants au Gluten. N.B.H. was supported by a grant from Le Réseau International des Instituts Pasteur. N.M. is supported by fellowships from Zonmw AGIKO and from the Nutricia Research Foundation.
2 M.B.A. and N.B.H. contributed equally to the work.
3 Address correspondence and reprint requests to Dr. Nadine Cerf-Bensussan, INSERM, Université Paris Descartes, Faculté de Médecine. 156 rue de Vaugirard, Paris, France. E-mail address: nadine.cerf-bensussan{at}inserm.fr
4 Abbreviation used in this paper: Treg, regulatory T cell.
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