UCSF

Apoptosis can regulate CD4+ T helper lymphocyte responses by eliminating dangerous, superfluous, and non-functional cells. I investigated the roles of Bim-dependent apoptosis in controlling the responses of CD4+ T cells exposed to a systemic self antigen, deprived of a growth factor, or transitioning from the effector to memory stages of an immune response.

Ova-specific DO11 TCR transgenic CD4+ T cells divide, then cease responding and die when transferred into sOva transgenic mice that express Ova as a systemic self antigen. Bim-deficient DO11 cells were equally activated but protected from death in sOva recipients. Both mRNA and protein expression of Bcl-2 family members suggested that apoptosis was triggered by a post-translational mechanism. Despite surviving, Bim-deficient DO11 cells ceased dividing, failed to produce cytokines, and caused no signs of autoimmune disease. This anergic phenotype was not caused by differentiation into FoxP3+ regulatory T cells and did not require CTLA-4 or PD-1. Instead, CD69 induction and a failure to re-express S1P1 may contribute to tolerance by trapping self-reactive T cells in lymphoid organs where constant antigen exposure causes anergy.

FoxP3+ regulatory T cells require IL-2 to survive, and IL-2-deficient mice develop fatal autoimmune anemia. Bim deficiency enabled FoxP3+ T cells to survive without IL-2 and promoted the survival of IL-2Rα negative DO11 FoxP3+ cells. However, mice lacking IL-2 and Bim still died of anemia, despite maintaining a normal percentage of FoxP3+ cells, and regulatory T cells from these animals suppressed poorly in an in vitro co-culture assay. Thus, regulatory T cells require IL-2 both to survive and to maintain their proper suppressive function.

Bim-deficient DO11 cells also survived the effector to memory transition of the CD4+ T cell responses to VSV-Ova infection and Ova-pulsed dendritic cell immunization. However, besides increasing the number of DO11 cells, Bim deficiency did not alter the effector or memory phenotypes. This suggests that memory cells are chosen by a stochastic process.