CTLA4‐Ig Restores Rejection of MHC Class‐II Mismatched Allografts by Disabling IL‐2‐Expanded Regulatory T Cells

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.