Parish Stanley T, Wu Jennifer E, Effros Rita B
Department of Pathology, David Geffen School of Medicine at University of California Los Angeles, 90095, USA.
J Immunol. 2009 Apr 1;182(7):4237-43. doi: 10.4049/jimmunol.0803449.
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-alpha 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-alpha 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-alpha 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-alpha 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-alphaR1 binding, increases in parallel with the loss of CD28 in long-term cultures, but this effect is blunted in the presence of the TNF-alpha 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.
缺乏CD28表达的CD8(+) T淋巴细胞群体扩增与多种有害临床结果相关，包括老年人的早期死亡、更快进展为艾滋病、心血管疾病以及肿瘤细胞生长增强。在细胞培养中，CD28表达的不可逆丧失与TNF-α产生增加相关，因为CD8(+) T细胞通过多轮抗原驱动的细胞分裂被驱动至复制衰老的非增殖终末期。有趣的是，在类风湿性关节炎患者中，TNF-α的抑制或中和可降低疾病关节中缺乏CD28的T细胞比例，这与表明该细胞因子直接参与CD28基因转录的研究一致。在此，我们表明，通过长期暴露于中和抗体或TNF-α受体-1抑制剂来调节人CD8(+) T淋巴细胞长期培养中的TNF-α水平，可增加增殖潜能、延迟CD28表达丧失、延缓细胞因子谱变化并增强端粒酶活性。我们还表明，TNF-αR1结合的下游效应器之一组成型caspase-3在长期培养中与CD28丧失平行增加，但在存在TNF-α抑制剂的情况下这种效应减弱。与体外培养数据一致，离体立即检测的CD8(+)CD28(-) T淋巴细胞与它们的CD28(+)对应物相比也显示出显著更高水平的caspase-3。这些发现有助于阐明CD28基因调控的复杂性质，并可能最终导致针对与CD28(-) T淋巴细胞比例增加相关疾病的新治疗方法。
