par Charbonnier, Louis-Marie ;Vokaer, Benoît ;Lemaitre, Philippe ;Field, Kenneth K.A.;Leo, Oberdan ;Le Moine, Alain
Référence American Journal of Transplantation, 12, 9, page (2313-2321)
Publication Publié, 2012-09
Article révisé par les pairs
Résumé : Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS+ Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade. CTLA4-Ig promotes CD4-mediated allograft rejection by counteracting a regulatory T cell-based protocol for tolerance induction. See editorial by Maltzman on page 2269. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

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