Postthymic development of CD28^-CD8⁺ T cell subset: Age-associated expansion and shift from memory to naive phenotype

During human aging, one of the major changes in the T cell repertoire is a dramatic expansion of T cells with the atypical CD28^-CD8⁺ phenotype. In this study, we show that this increase is a consequence not only of an expansion in the CD28^-CD8⁺ population but also of a decrease in the number of CD28⁺CD8⁺ T cells. The decrease in circulating CD28⁺CD8⁺ T cells is dramatically accelerated after the age of 50 and is not accompanied by an equivalent reduction in the CD28⁺CD4⁺ subset. Our findings confirm that aging leads to an accumulation of CD45RO⁺ T cells within the CD28⁺CD8⁺ subset as previously observed. Surprisingly, we found an increase in CD45RA⁺ expression with age in the CD28^-CD8⁺ subset. Immune-phenotyping for activation markers, measurement of telomere DNA content, and cytokine production analysis indicate that the large majority of CD28^-CD8⁺ T cells are Ag-experienced, despite their CD45RA⁺ phenotype. Our study further demonstrates that the poor proliferative response displayed by CD28^-CD8⁺ T cells is not a consequence of telomere shortening. Also, analysis of cytokine production at the single cell level revealed that the proportions of IFN- γ⁺, IL-4⁺, and IL-10⁺ T cells are considerably higher among the CD28^- CD8⁺ than the CD28+CD8+ subset. In summary, these data explain the presence of CD45RA⁺ T cells in the elderly, shed light on the phylogenetic origin of CD28^-CD8⁺ T cells, and suggest a role for these cells in the immune senescence process.