Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes.
CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.
Parish
Stanley T
ST
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Wu
Jennifer E
JE
Effros
Rita B
RB
D000375:Aging / Q000276:immunology*; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016922:Cellular Senescence / Q000276:immunology*; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D015398:Signal Transduction / Q000276:immunology
D018106:CD28 Antigens