Distinct activation programs in naïve and memory CD8 T cells govern progeny stemness and effector persistence (multiome, OT-I. Day 0 as control, Day 7 and Day 12)

We longitudinally profiled gene expression in naive and central and effector memory CD8+ T cells across multiple models of acute cognate infection to reveal subset-specific activation programs. However, how prior antigen experience alters T-cell activation programs remains poorly understood. We longitudinally profiled gene expression in naive, central memory, and effector memory CD8+ T cells in response to cognate antigen across multiple models of acute infection. Naive T cells engaged TOX- and TCF7-centered programs and generated early stem-like central memory precursors. Their initially slow proliferation was followed by rapid expansion and the production of large numbers of effector cells. Central memory T cells rapidly triggered effector and proliferation programs while maintaining a smaller self-renewing population. Effector memory T cells expanded poorly and generated almost exclusively effector progeny. Effector progeny derived from both memory subsets survived contraction more efficiently than naive T-cell-derived progeny and established persistent effector memory populations. These data show that prior antigen experience does not simply accelerate CD8+ T-cell activation but redirects cell-intrinsic programs governing progeny fate and persistence. These distinct programs may reflect adaptation to different histories and anticipated patterns of antigen exposure.