Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans.

The impact of intrinsic aging upon human peripheral blood T cell subsets remains incompletely quantified and understood. This impact must be distinguished from the influence of latent persistent microorganisms, particularly CMV, which has been associated with age-related changes in the T cell pool. In a cross-sectional cohort of 152 CMV-negative individuals, aged 21-101 y, we found that aging correlated strictly to an absolute loss of naive CD8, but not CD4, T cells but, contrary to many reports, did not lead to an increase in memory T cell numbers. The loss of naive CD8 T cells was not altered by CMV in 239 subjects (range 21-96 y), but the decline in CD4(+) naive cells showed significance in CMV(+) individuals. These individuals also exhibited an absolute increase in the effector/effector memory CD4(+) and CD8(+) cells with age. That increase was seen mainly, if not exclusively, in older subjects with elevated anti-CMV Ab titers, suggesting that efficacy of viral control over time may determine the magnitude of CMV impact upon T cell memory, and perhaps upon immune defense. These findings provide important new insights into the age-related changes in the peripheral blood pool of older adults, demonstrating that aging and CMV exert both distinct and joint influence upon blood T cell homeostasis in humans.

Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates.

Aging is usually accompanied by diminished immune protection upon infection or vaccination. Although aging results in well-characterized changes in the T cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary Ag responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naive T cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of TCR repertoire limit the Ag responses in aging primates. We show in this study that aging rhesus monkeys (Macaca mulatta) exhibit poor CD8 T cell and B cell responses in the blood and poor CD8 responses in the lungs upon vaccination with the modified vaccinia strain Ankara. The function of APCs appeared to be maintained in aging monkeys, suggesting that the poor response was likely intrinsic to lymphocytes. We found that the loss of naive CD4 and CD8 T cells, and the appearance of persisting T cell clonal expansions predicted poor CD8 responses in individual monkeys. There was strong correlation between early CD8 responses in the transitory CD28+ CD62L- CD8+ T cell compartment and the peak Ab titers upon boost in individual animals, as well as a correlation of both parameters of immune response to the frequency of naive CD8+ T cells in old but not in adult monkeys. Therefore, our results argue that T cell repertoire constriction and naive cell loss have prognostic value for global immune function in aging primates.

Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates.

The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G(1)-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.

Molecular, cellular, and antigen requirements for development of age-associated T cell clonal expansions in vivo.

T cell aging manifests itself both at the cellular (cell-autonomous defects in signaling) and at the population (age-related dysregulation of T cell homeostasis) levels. A prominent contributor to the latter is the appearance of T cell clonal expansions (TCE), with a potential to impair immune defense. In this study, we investigated molecular, cellular, and Ag requirements for TCE development. Of the mutant mice tested, old animals lacking MHC class I exhibited 7-fold fewer TCE than controls, with a 7-fold reduction in TCE. By contrast, animals lacking only one of the MHC class I molecules (Kb or Db), or IL-7R, or devoid of T cell renewal via adult thymectomy, all exhibited significant increases in TCE incidence. This increase directly correlated to lymphopenia, increased CD8 T cell turnover and an accumulation of memory-phenotype T cells. These data suggested that homeostatic cell division in the CD8 compartment enhances the formation of TCE. Repeated immunization with peptide/adjuvant did not result in an increase in Ag-specific TCE; however, adjuvant alone increased TCE incidence. In these experiments, therefore, nonspecific and/or homeostatic proliferation was more efficient in generating TCE in mice than repeated Ag-driven stimulation, suggesting that many, if not most, TCE in specific pathogen-free laboratory mice may be Ag-independent.