Two Separate Defects Affecting True Naive or Virtual Memory T Cell Precursors Combine To Reduce Naive T Cell Responses with Aging

Abstract

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.

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

“…However, Tim‐3 − PD‐1 + cells display moderate levels of expression, meaning they are a rather mixed population that can be generated by antigen‐dependent or antigen‐independent mechanisms. With aging, the virtual memory cells, defined by their low expression of CD49d, also accumulate (Chiu et al ., 2013; Renkema et al ., 2014). We found that the majority of virtual memory cells belong to the Tim‐3 − PD‐1 − population.…”

Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8 + T cells in aged mice

“…In young adult mice, naïve CD44hi T VM cells represent a distinct subset, characterized by markers of homeostatic proliferation, exquisite sensitivity to cytokine stimulation, and arising independently of antigenic stimulation (31,32). Naïve CTLps with a T VM phenotype accumulate with age (14,16), an effect that is only seen for TCR transgenic animals if the endogenous TCRα is free to rearrange, indicating a requirement for TCR-mediated signals (6). However, when we used TCR sequencing analysis to assess the age-related repertoire (for D b PB1-F2 62 ) at the individual cell level, there was no evidence that clonal expansion is associated with either age or T VM phenotype, because the TCR repertoires at all ages remained completely diverse and were not dominated by selective clonal expansions.…”

“…Although we found no evidence of proliferation for CD44hi CTLps from young or aged mice, experiments by others have indicated that the expression of particular TCRs may drive the acquisition of a CD44hi phenotype. In particular, Renkema et al found that age-related accumulation of CD44hi cells only occurred in TCR transgenic animals if the endogenous TCRα chain was free to rearrange (6).…”

“…Normal aging is associated with increased health risk, as vaccine efficacy wanes and susceptibility to, and severity of, a variety of infections and malignancies is enhanced (1,2). Whereas aging compromises a number of arms of the immune system (3), studies in mice and humans have demonstrated deficits that are intrinsic to naïve CTL populations (4)(5)(6). Thus, a complete understanding of both age-related CTL deficiencies and the underlying mechanisms is critical.…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…Recent studies in animal models further suggest qualitative alterations in the naïve T‐cell compartment and impaired induction of de novo T‐cell responses with age (Brien et al ., 2009; Cicin‐Sain et al ., 2010; Smithey et al ., 2011; Renkema et al ., 2014). Indeed, contraction of the murine naïve T‐cell repertoire can impair T‐cell responses to immunodominant epitopes (Yager et al ., 2008; Valkenburg et al ., 2012).…”