Two separate defects affecting true naïve (TNa) or virtual memory (VM) T cell precursors combine to reduce naïve T cell responses with aging

摘要

Naïve T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ≥70% of Ag-specific CD8 T cell precursors and that many of the remaining precursors acquire a “virtual (central) memory” (VM; CD44^hiCD62L^hi) phenotype. Here, we demonstrate that unimmunized T cell receptor (TCR) transgenic (Tg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended upon replacement of the original TCRTg specificity by endogenous TCRα rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild type and old TCRTg mice - old VM, but not old true naïve, T cells exhibited blunted TCR-mediated, but not IL-15-mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 & IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and demonstrate that two separate age-related defects – drastic reduction in true naïve T cell precursors and impaired proliferative capacity of their VM cousins –combine to reduce naïve T cell responses with aging.