CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade

Abstract

Blockade of costimulatory signals is a promising therapeutic target to prevent allograft rejection. In this study, we sought to characterize to what extent CTLA-4 engagement contributes to the development of transplantation tolerance under the cover of CD40/CD40L and CD28/CD86 blockade. In vitro, we found that inhibition of the primary alloresponse and induction of alloantigen hyporesponsiveness by costimulation blockade was abrogated by anti-CTLA-4 mAb. In addition, regulatory CD4+CD25+ T cells (TREG) were confirmed to play a critical role in the induction of hyporesponsiveness by anti-CD40L and anti-CD86 mAb. Our data indicated that CTLA-4 engagement is not required for activation or suppressor function of TREG. Instead, in the absence of either CTLA-4 signaling or TREG, CD8+ T cell division was enhanced, whereas the inhibition of CD4+ T cell division by costimulation blockade remained largely unaffected. In vivo, the administration of additional anti-CTLA-4 mAb abrogated anti-CD40L- and anti-CD86 mAb-induced cardiac allograft survival. Correspondingly, rejection was accompanied by enhanced allograft infiltration of CD8+ cells. We conclude that CTLA-4 signaling and TREG independently cooperate in the inhibition of CD8+ T cell expansion under costimulation blockade.