Work

Defining mechanisms of heterogeneous restimulation-induced cell death sensitivity across human T cell populations 3063

Year: 2025

Type: article

Abstract: Description Restimulation-Induced Cell Death (RICD) is a critical self-regulatory apoptosis pathway that prevents excessive accumulation of activated effector T cells during an adaptive immune response, governed in part by de novo gene transcription. Underlying mechanisms that explain highly variable RICD sensitivity in effector T cells derived from different human donors remain poorly understood. We hypothesize that distinct cell surface markers and gene expression programs govern relative RICD sensitivity of specific subsets of effector T cells within and across human donors. To test this hypothesis, we have amassed extensive phenotypic data on both fresh and cryopreserved effector T cells derived from >50 healthy human donors. By employing spectral flow cytometry, we detected enrichment of senescence and exhaustion markers in donor T cell populations with greater RICD sensitivity. Conversely, more naive and central memory T cells are observed in initial cultures from RICD resistant donors. By validating these results using scRNA-seq, we are generating unbiased, mechanism-based hypotheses aimed at defining gene expression programs that govern RICD sensitivity between specific effector T cell subsets. Our work will ultimately construct an “atlas” of human RICD variability that can be used to elucidate and predict relative RICD susceptibility across donors, informing new approaches to understand T cell responses to infection/immunization and optimize adoptive T cell immunotherapies. Funding Sources Supported by NIH R35GM139619. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.903