Differential role of Bcl-2 in CD8+and CD4+T cell homeostasis

Abstract Regulated induction of apoptosis is critical for normal functioning of the adaptive immune system. Both TCR/MHC interactions and by soluble cytokines maintain T cells via their ability to modulate Bcl-2 family members, although the dependence of CD4+ and CD8+ T cells upon individual anti-apoptotic molecules remains unclear. Here, we used mice with a conditional allele of Bcl-2 crossed with dLck-Cre mice to assess the role of Bcl-2 in CD4+ and CD8+ T cell survival. We found that dlck-Cre-driven deletion of Bcl-2 resulted in a massive loss of naïve CD8+ T cells, but only a modest loss of naïve CD4+ T cells. We next tested if Bcl-2 was important for effector CD4+ T cell survival after infection with lymphocytic choriomeningitis virus (LCMV). Interestingly, the majority of LCMV-specific CD4+ T cells did not require Bcl-2 to survive contraction of the response. Further, treatment of mice with ABT-737, a Bcl-2, Bcl-xL, and Bcl-w inhibitor, only modestly increased the loss of effector CD4+ T cells, suggesting that neither Bcl-2, Bcl-xL, nor Bcl-w are required for survival of effector CD4+ T cells. Instead, we find that the Bcl-2 family member, A1 is increased in effector CD4+ T cells and we are currently investigating the role of A1 in the survival of naïve and activated CD4+ T cells. As the pro-apoptotic Bcl-2 family member Bim is critical to control naïve and effector CD4+ T cells, A1 may be an important Bim antagonist that promotes effector CD4+ T cell responses.