Differential apoptosis sensitivity of human effector CD8+ T cells derived from central versus effector memory subsets in response to IL-2 withdrawal

Abstract

Abstract CD8+ central memory (CM) and effector memory (EM) T cell subsets exhibit well-established differences in proliferative and protective capacity after infectious challenge. However, their relative sensitivity to apoptosis has been largely overlooked, despite the importance of programmed cell death in regulating effector T cell homeostasis. Here we demonstrate that primary human effector T cells derived from the CD8+ EM subset exhibit significantly higher sensitivity to cytokine withdrawal induced cell death (CWID), a critical intrinsic apoptosis program responsible for culling cells once an infection is cleared and interleukin-2 (IL-2) levels diminish. Interestingly, we found no differences in the expression of IL-2 or IL-2 receptor components in cells originating from either subset. Relative to CM-derived effectors, however, EM-derived T cells display more mitochondrial instability and greater basal caspase activation. Indeed, we found that heightened CWID sensitivity in EM-derived effectors is linked to higher expression of the pro-apoptotic Bcl-2 family protein BIM, both at steady state and with de novo induction following withdrawal of exogenous IL-2. These data point to “imprinted” differences in BIM protein regulation preserved between CD8+ CM and EM progeny that govern their relative sensitivity to CWID. These findings offer new insight into why CM-derived T cells display superior effector cell expansion and more persistent memory responses in vivo relative to EM-derived T cells, based on differential apoptosis sensitivity.