Subset-specific and temporal control of effector and memory CD4+ T cell survival.

Following their proliferative expansion and differentiation into effector cells like Th1, Tfh, and T central memory precursors (Tcmp), most effector CD4+ T cells die, while some survive and become memory cells. Here, we explored how Bcl-2 family members controlled the survival of CD4+ T cells during distinct phases of mouse acute LCMV infection. During expansion, we found that Th1 cells dominated the response, downregulated expression of Bcl-2, and did not require Bcl-2 for survival. Instead, they relied on the anti-apoptotic protein, A1 for survival. Similarly, Th17 cells in an EAE model also depended on A1 for survival. However, after the peak of the response, CD4+ effector T cells required Bcl-2 to counteract Bim to aid their transition into memory. This Bcl-2 dependence persisted in established memory CD4+ T cells. Combined, these data show a temporal switch in Bcl-2 family-mediated survival of CD4+ T cells over the course of an immune response. This knowledge can help improve T cell survival to boost immunity and conversely, target pathogenic T cells.