Unbiased Multiparameter Analyses Reveal Mechanisms of Variable Restimulation-Induced Cell Death Sensitivity across Human T cell Populations 2251586

作者：Benjamin Epstein, Melissa Kallarakal, Katherine Lee, Camille Alba, Elizabeth Rice, Clifton Dalgard, Andrew Snow · 发表于：The Journal of Immunology · 年份：2026 · DOI：10.1093/jimmun/vkag141.121 · 研究领域：CAR-T cell therapy research、T-cell and B-cell Immunology、Phagocytosis and Immune Regulation

Abstract Introduction Restimulation-Induced Cell Death (RICD) is a crucial self-regulatory apoptosis pathway that constrains effector T cell expansion during an adaptive immune response. Our lab and others have implicated multiple genes involved in regulating RICD sensitivity, but molecular mechanisms that explain highly hetergeneous RICD susceptibility across healthy human donors remain nebulous. We hypothesized that relative RICD sensitivity could be explained by specific gene expression programs that correspond to functional differentiation states of multiple, distinct effector T cell subsets. Methods We took an unbiased approach to this question by amassing extensive phenotypic data on T cells collected from >50 healthy human donors, employing spectral flow cytometry and scRNA-seq on effector T cells from the most highly resistant vs. sensitive individuals. Results Our results unveiled enrichment of CD8+ T cells expressing senescence (CD57, NKG2D) and exhaustion (TIGIT) markers in highly sensitive donors; indeed, FACS-based purification confirmed CD8+CD57+ T cells were markedly more susceptible to RICD compared to CD57- counterparts. Moreover, scRNA-seq revealed upregulation of PI-3K pathway genes in RICD sensitive donors, consistent with enhanced PI-3K signaling in senescent T cells. RICD sensitive donors also harbored more “aged” CD4+ T cells expressing ZEB2 and cytotoxicity genes (PRF1, GZMB/K, GNLY, NKG7). Conversely, RICD-resistant CD4+ and CD8+ effector T cel...