Differential restimulation-induced cell death sensitivity between CD8+ memory T cell subsets (LYM4P.754)

Abstract

Abstract CD8+ central memory (CM) and effector memory (EM) T cell subsets exhibit well-established differences in longevity and protective capacity after infectious challenge. However, their respective sensitivity to cell death has been overlooked, despite its importance in maintaining immune homeostasis. Here we show that effector T cells derived from sorted human CD8+ CM and EM subsets demonstrate differential sensitivity to T cell receptor (TCR) restimulation induced cell death (RICD), a critical self-regulatory apoptosis pathway for constraining excessive T cell expansion. By quantitating differences in AnnexinV binding, mitochondrial membrane potential and caspase activation, we found that EM-derived effector T cells are significantly more sensitive to RICD than CM-derived effectors, whereas responses to other extrinsic or intrinsic apoptotic stimuli were equivalent. Our data suggests that EM-derived effectors demonstrate a stronger, more robust TCR signal, via enhanced LCK activity, for potent RICD induction. These data point to “imprinted” TCR signaling differences preserved between CD8+ CM and EM progeny that govern their relative sensitivity to RICD. Our findings offer new insight into why CM-derived T cells display superior effector expansion and persistent memory responses in vivo, beyond simple proliferation capacity. Moreover, our use of primary human T cell subsets is a novel comparative approach for defining molecular mechanisms that control RICD sensitivity.