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CTLA-4 Engagement and Regulatory CD4⁺CD25⁺ T Cells Independently Control CD8⁺-Mediated Responses under Costimulation Blockade¹

Jeroen J. A. Coenen^*, Hans J. P. M. Koenen^*, Esther van Rijssen^*, Louis Boon, Irma Joosten^* and Luuk B. Hilbrands^2,

^* Department of Bloodtransfusion and Transplantation Immunology and Department of Nephrology, University Medical Center Nijmegen, Nijmegen, The Netherlands; and Bioceros, Utrecht, The Netherlands

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 (T_REG) 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 T_REG. Instead, in the absence of either CTLA-4 signaling or T_REG, 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 T_REG independently cooperate in the inhibition of CD8⁺ T cell expansion under costimulation blockade.

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