Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): Differential behavior of CD4 and CD8 subsets

A prominent theory of immune senescence holds that repeated antigenic stimulation and decreased production of naive cells combine to progressively exhaust the reserve of lymphocytes available to fight new pathogens, culminating in an accumulation of lymphocytes that achieved replicative senescence. A well-defined primate model of immune senescence in vivo would greatly facilitate testing of this theory. Here, we investigated phenotypic and functional T-cell aging in the rhesus macaques (RMs), currently the dominant primate model of AIDS. Our results show that sharp differences exist between the CD8 and CD4 T-cell subsets in (1) cell-cycle programs (as assessed by both in vitro proliferation and in vivo turnover measurement); (2) CD28 regulation on cell-cycle entry; and (3) accumulation of immediate effector cells among the CD28^- cells, believed to be close to or at replicative senescence. These results further suggest poor reliability of CD28 as a marker for senescence. We suggest that some of the T-cell aging phenomenology in RMs can be ascribed to accentuation over time of the inherent differences in activation programs in CD8 and CD4 T cells.