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; CD44hiCD62Lhi) 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.

Studies of CD8 T cell responses to vaccination or infection with various pathogens in both animal models and human subjects have revealed a markedly consistent array of age-related defects. In general, recent work shows that aged CD8 T cell responses are decreased in magnitude, and show poor differentiation into effector cells, with a reduced arsenal of effector functions. Here we review potential mechanisms underlying these defects. We specifically address phenotypic and numeric changes to the naïve CD8 T cell precursor pool, the impact of persistent viral infection(s) and inflammation, and contributions of the aging environment in which these cells are activated.

Summary Aging is accompanied by altered immunity, resulting in a variable state of poorly understood immunodeficiency. While both the numbers and the functionality of naïve T-cells are decreased by aging, the impact of these changes upon immune defense against bacterial pathogens in vivo remains understudied. Using a model of Listeria monocytogenes (Lm), where the primary CD8 T-cell response is critically important for immune defense, we show that C57BL/6 (B6) mice exhibit an age-dependent reduction in survival, with delayed bacterial clearance in old animals. Kinetic analysis of antigen-specific CD8 T-cell expansion showed that CD8 effectors begin dividing at the same time in old and adult mice, but that the proliferative burst remained incomplete during discrete windows of time and was coupled with increased effector apoptosis in old mice. Further, antilisterial CD8 T-cells in old mice showed altered expression of key phenotypic and effector molecules and diminished polyfunctionality, measured by the ability to simultaneously produce multiple effector molecules. These results suggest that defects in functional maturation of CD8 cells in aged mice, compounded by (or perhaps coupled to) their reduced expansion in response to infection, yield effector CD8 T-cell populations insufficient in size and capability to effectively clear newly encountered intracellular pathogens.

Aging of the world population and a concomitant increase in age-related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age-related decline of the immune system, infectious diseases remain among the top 5–10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan.

CD8 effector T cells with a CD127 hi KLRG1 2 phenotype are considered precursors to the long-lived memory pool, whereas KLRG1 + CD127 low cells are viewed as short-lived effectors. Nevertheless, we and others have shown that a KLRG1 + CD127 low population persists into the memory phase and that these T cells (termed long-lived effector cells [LLEC]) display robust protective function during acute rechallenge with bacteria or viruses. Whether these T cells represent a true memory population or are instead a remnant effector cell population that failed to undergo initial contraction has remained unclear. In this study, we show that LLEC from mice express a distinct phenotypic and transcriptional signature that shares characteristics of both early effectors and long-lived memory cells. We also find that in contrast to KLRG1 + effector cells, LLEC undergo homeostatic proliferation and are not critically dependent on IL-15 for their maintenance. Furthermore, we find that LLEC are predominantly derived from KLRG1 + effector cells when isolated at day 12 of the response. Our work challenges the concept that the KLRG1 + CD127 low population is dominated by short-lived cells and shows that KLRG1 downregulation is not a prerequisite to become a long-lived protective memory T cell.