Maintaining CD28 expression prevents replicative senescence in human CD 8 T cells (50.23)

Abstract

Abstract The irreversible loss of expression of the CD28 costimulatory receptor is one of the signature changes in human T cells that are driven to the end stage of replicative senescence by chronic stimulation in cell culture. Besides activation, CD28 is also required for glucose metabolism, stabilization of various cytokine mRNAs, and, importantly, for optimal upregulation of telomerase, the enzyme that stabilizes telomeres. Increased proportions of senescent CD8 T cells are associated with decreased vaccine responsiveness and early mortality in the elderly, and, during HIV disease, with more rapid progression to AIDS. Previous work showed that inhibition of TNFα, which allowed for prolonged CD28 expression, delayed the onset of senescence. In the present study, CD8 T cells were stably transduced with CD28, and compared to empty-vector transduced control cultures. Maintaining continuous CD28 expression led to the significantly increased proliferative potential and sustained telomerase activity. Furthermore, IL-2 and IFNγ message levels were increased, and TNFα and IL-6, cytokines that are significantly increased at replicative senescence, were undetectable by ELISA at 25 population doublings, the time-point at which the control cultures reached senescence. These data underscore the central role of CD28 in memory CD8 T cell biology, and suggest a possible new therapeutic approach for enhancing immune function during aging and AIDS. (Supported by NIH AG023720 & AI060362).