Manipulaion of TNFalpha delays loss of CD28 expression in human CD8 T cells (96.19)

Abstract

Abstract The CD28 costimulatory receptor is essential for T cell activation, glucose metabolism, and optimal telomerase activity. Increased proportions of CD8+CD28 T cells, seen in HIV infection and aging, correlate with decreased vaccine responsiveness and early mortality. CD28 expression is also lost in chronically stimulated cultures of CD8 T cells as they approach replicative senescence, a state of irreversible cell cycle arrest, associated with shortened telomeres and increased levels of TNFα. Based on the link between TNFα and the CD28 gene promoter, we sought to investigate the effects of manipulating TNFα on replicative senescence. Human T cells were repeatedly stimulated with an allogeneic cell line in the presence of either a neutralizing antibody (anti-TNFα) or a TNFα receptor 1 inhibitor (rhuTNFR:Fc). CD28 expression and gene transcription were monitored by flow cytometry and RT-PCR, respectively. Chronic exposure of antigen-stimulated CD8 T cells to rhuTNFR:Fc or anti-TNFα delayed the loss of CD28 expression. Even after completing 17 population doublings, the treated cultures contained >20% more CD28+ cells; CD28 gene transcription was similarly elevated. Finally, telomerase activity was increased by as much as 6-fold in the treated cultures. Manipulation of TNFα, therefore, may be a useful clinical approach to delay accumulation of senescent CD8 T cell in vivo. Supported by NIH AI060362 and AG023720