title: CTLA4-Ig restores rejection of MHC class-II mismatched allografts by disabling IL-2-expanded regulatory T cells.
abstract: 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.
authors: Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium. lm.charbonnier@free.fr
authors: L-M
authors: LM
authors: Charbonnier
authors: B
authors: B
authors: Vokaer
authors: P H
authors: PH
authors: Lemaître
authors: K A
authors: KA
authors: Field
authors: O
authors: O
authors: Leo
authors: A
authors: A
authors: Le Moine
mesh_terms: D000069594:Abatacept; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006650:Histocompatibility Testing; D018796:Immunoconjugates / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D007376:Interleukin-2; D000069594:Abatacept