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Modulation of T Lymphocyte Replicative Senescence via TNF- Inhibition: Role of Caspase-3¹

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095

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 TNF- as 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 TNF- reduces 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 TNF- levels in long-term cultures of human CD8⁺ T lymphocytes, by chronic exposure either to a neutralizing Ab or to an inhibitor of the TNF- receptor-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 TNF-R1 binding, increases in parallel with the loss of CD28 in long-term cultures, but this effect is blunted in the presence of the TNF- inhibitors. 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grants AG023720 and AI060362 (to R.B.E.).

² Address correspondence and reprint requests to Rita B. Effros, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: reffros{at}mednet.ucla.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; PD, population doubling; R1 inhibitor, an inhibitor of the TNF- receptor-1; TRAP, telomeric repeat amplification protocol.