*Purpose: T cell activation and effector differentiation precede graft rejection, and this process is associated with robust metabolic burst to meet the energy demand of activated T cells. This metabolic burst also produces tremendous reactive oxygen species (ROS) that must be reduced in a timely fashion in dividing cells to ensure effector functions. In the present study we examined whether modulating the Redox pathway would promote transplant survival.

*Methods: A BALB/c to C57BL/6 (B6) heart transplantation model was adopted to evaluate the function of apurinic/apyrimidinic endonuclease 1 (APEX1), a major nuclear redox regulator and a rate-limiting enzyme that is responsible for repairing ROS-induced DNA damage, in transplantation tolerance induction by using CD4^creApex1^fl/fl mice. In vivo Graft-infiltrating immune cells and in vitro cultured CD4+ T cells were also analyzed for mechanistic studies.

*Results: We found that in T cells that infiltrated the heart allografts, expression of APEX1 was markedly increased, which was correlated with the enhanced production of ROS by the graft infiltrating T cells. We also found that T cell specific deletion of Apex1 did not affect thymocyte development and peripheral T cell homeostasis but activated T cells failed to acquire effector functions and readily committed to apoptotic cell death, and the death of Apex1 deficient T cells could be rescued by ROS scavengers in vitro. In a Balb/c to B6 heart transplant model, CTLA-4Ig treated Wt B6 mice chronically rejected the heart allografts, but the similarly treated CD4^creApex1^fl/fl mice uniformly accepted the heart allografts long-term (>100 days). Mechanistically, deficiency of Apex1 inhibited mitochondrial respiration by down-regulating Ndufs5, which boosted ROS production. This oxidative stress induced apoptotic death of activated T cells.

*Conclusions: Our data identified APEX1 as a novel critical regulator of T effector cells that can be targeted for the induction of transplant survival.

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