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Distinct activation programs in naïve and memory CD8 T cells govern progeny stemness and effector persistence (bulk experiment, NupHox mice, Lm-OVA infection)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE339513 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.

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Distinct activation programs in naïve and memory CD8 T cells govern progeny stemness and effector persistence (bulk experiment, NupHox mice, Lm-OVA infection)

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