Modulation of T Lymphocyte Replicative Senescence via TNF- Inhibition: Role of Caspase-3

Expanded populations of CD8 T lymphocytes lacking CD28 expression are associated with a variety of deleterious clinical outcomes, including early mortality in the elderly, more rapid progression to AIDS, cardiovascular disease, and enhanced tumor cell growth. In cell culture, irreversible loss of CD28 expression correlates with increased production of TNFas CD8 T cells are driven to the nonproliferative end stage of replicative senescence by multiple rounds of Ag-driven cell division. Interestingly, in patients with rheumatoid arthritis, inhibition or neutralization of TNFreduces the proportion of T cells lacking CD28 in the disease joints, consistent with studies showing a direct involvement of this cytokine in CD28 gene transcription. Here, we show that modulation of TNFlevels in long-term cultures of human CD8 T lymphocytes, by chronic exposure either to a neutralizing Ab or to an inhibitor of the TNFreceptor-1, increases proliferative potential, delays loss of CD28 expression, retards cytokine profile changes, and enhances telomerase activity. We also show that constitutive caspase-3, one of the downstream effectors of TNFR1 binding, increases in parallel with the loss of CD28 in long-term cultures, but this effect is blunted in the presence of the TNFinhibitors. Consistent with the in vitro culture data, CD8 CD28 T lymphocytes tested immediately ex vivo also show significantly higher levels of caspase-3 compared with their CD28 counterparts. These findings help elucidate the complex nature of CD28 gene regulation, and may ultimately lead to novel therapeutic approaches for diseases associated with increased proportions of CD28 T lymphocytes. The Journal of Immunology, 2009, 182: 4237– 4243.