MiR-23a supports survival of activated CD4+ T cells by maintaining reactive oxygen species equilibrium (IRM5P.638)

Abstract

Abstract To identify key miRNAs that regulate CD4+ T cell responses, we profiled miRNA expression in CD4+ T cells at different phases post-antigen stimulation. As miR-23a is a miRNA that correlated strongly with effector CD4+ T cell expansion, we generated a T-cell specific miR-23a knockout mouse line (23T-KO). We found that miR-23a in T cells is essential for effective anti-bacteria protection, as the loss of effector T cells during the early phase of antigen activation rendered 23aT-KO mice susceptible to high-dose listeria infection. As early as a few hours post-activation in vitro, naïve 23T-KO CD4+ T cells exhibit an accelerated death, which is not rescued by caspase inhibition. Further analysis reveal that miR-23a deficiency in CD4+ T cells severely impairs their mitochondrial structural and functional integrity; Consequently, TCR activation of 23T-KO CD4+ T cells induce the rapid loss of mitochondrial potential and accumulation of reactive oxygen species. Forced expression of the antioxidant enzyme GPX1 protects activated naïve 23T-KO T cells from accelerated cell death. Mechanistically, we determine that miR-23a loss results in the accumulation of its direct target, PPIF, a structural component of the mitochondria permeability transition pore complex. Taken together, our results indicate that PPIF-controlled ROS equilibrium is essential for the survival of effector CD4+ T cells, and that miR-23a is indispensable for maintaining ROS homeostasis during early antigen activation.