Nonrandom attrition of the naive CD8 ⁺ T-cell pool with aging governed by T-cell receptor:pMHC interactions

Abstract

Immunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and diversity of naive CD8 + T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor: pMHC avidity, and preferentially acquired "memory-like" phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and diversity defects in old T cells.lymphocyte homeostasis | T-cell repertoire | CD8 T cells

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

“…Data obtained from a variety of species (6)(7)(8)(9)(10)(11)16) indicate that the effective clonal diversity of T cells declines with age. Using CDR3 amino acid sequences obtained from the TCR b-chain (16), we estimated the age-dependent change in the effective clonal diversity of naive CD4/CD8 T cells found in human blood (Fig.…”

“…In aged mice, the CD8 T cell repertoire is biased in favor of T cells with a high avidity for self-peptide MHC (8). These T cells preferentially undergo homeostatic proliferation, leading to a contraction of T cell repertoire diversity in aged mice (8).…”

“…In aged mice, the CD8 T cell repertoire is biased in favor of T cells with a high avidity for self-peptide MHC (8). These T cells preferentially undergo homeostatic proliferation, leading to a contraction of T cell repertoire diversity in aged mice (8). Numerical simulations (21) suggest, however, that this unequal homeostatic proliferation rates alone may be insufficient to cause the sharp decline of T cell diversity observed in elderly humans.…”

“…The magnitude of the T cell response to a newly encountered Ag depends strongly on the frequencies of naive T cell clones that have specificity for that Ag (4,5). However, the clonal diversity of naive T cells decreases with age (6)(7)(8)(9)(10)(11), resulting in the loss of Ag-specific clones. This leads to a failure of the immune system to recognize certain Ags, including pathogen derived (12), and a higher probability that recognized Ags will subsequently acquire mutations that abrogate their recognition (13).…”

Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age

“…Though individual T cells bind and recognize one or at most a few epitopes via their T-cell receptor (TCR), the entire population of T cells encompasses a diverse repertoire of TCRs that, ideally, allows recognition of the epitopes on essentially any pathogen. The diversity of this repertoire declines over time, as demonstrated by experimental work in aged mice (1)(2)(3), rhesus macaques (4), and humans (5). This decline in diversity has implications for susceptibility to disease, yet, as we explore in this paper, the driving forces underlying this decline remain unclear.…”