Copeland K F, Haaksma A G, Goudsmit J, Krammer P H, Heeney J L
Laboratory of Viral Pathogenesis, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
AIDS Res Hum Retroviruses. 1994 Oct;10(10):1259-68. doi: 10.1089/aid.1994.10.1259.
This study set out to determine whether T cell dysfunction associated with HTLV-I led to increased sensitivity of infected cells to apoptosis or, owing to their potential to develop ATL, if infected cells would become resistant to this process. To test this hypothesis we utilized the monoclonal antibody anti-APO-1, which has been demonstrated to induce apoptosis in human T cells. Human T cell lines expressing HTLV-I showed reduced susceptibility to anti-APO-1-induced apoptosis despite expression of high levels of cell surface APO-1. Cell-free supernatant of the Tax-expressing cell line C8166 and heat-inactivated supernatant of the HTLV-I-producing cell line MT2 transferred increased resistance to anti-APO-1 to susceptible Jurkat T cells. Susceptible T cells transfected with an HTLV-I Tax-expressing vector or treated with soluble Tax protein became less susceptible to anti-APO-1-induced cell death. Furthermore, primary human lymphocytes treated with soluble Tax were less susceptible to apoptosis induced by anti-APO-1. The protective effect of Tax in T cell lines and primary human lymphocytes was reversed by the addition of anti-Tax antibodies. Anti-APO-1-induced apoptosis was also found to be inhibited in Jurkat cells by the induction of protein kinase C (PKC) with 12-O-tetradecanoylphorbol-13-acetate (TPA). Resistance to apoptosis conferred by HTLV-I Tax and an active PKC pathway may be factors contributing to the survival of dysregulated HTLV-I-infected T cells prone to the development of adult T cell leukemia.
本研究旨在确定与人类嗜T淋巴细胞病毒I型（HTLV-I）相关的T细胞功能障碍是否会导致受感染细胞对细胞凋亡的敏感性增加，或者由于它们发展为成人T细胞白血病（ATL）的可能性，受感染细胞是否会对这一过程产生抗性。为了验证这一假设，我们使用了单克隆抗体抗APO-1，该抗体已被证明可诱导人类T细胞凋亡。表达HTLV-I的人类T细胞系尽管细胞表面APO-1表达水平很高，但对抗APO-1诱导的凋亡敏感性降低。表达Tax的细胞系C8166的无细胞上清液和产生HTLV-I的细胞系MT2的热灭活上清液将对APO-1的抗性增加传递给了敏感的Jurkat T细胞。用表达HTLV-I Tax的载体转染或用可溶性Tax蛋白处理的敏感T细胞对抗APO-1诱导的细胞死亡敏感性降低。此外，用可溶性Tax处理的原代人淋巴细胞对抗APO-1诱导的凋亡敏感性较低。添加抗Tax抗体可逆转Tax在T细胞系和原代人淋巴细胞中的保护作用。用12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导蛋白激酶C（PKC）也可抑制Jurkat细胞中抗APO-1诱导的凋亡。HTLV-I Tax和活跃的PKC途径赋予的抗凋亡能力可能是导致易于发展为成人T细胞白血病的失调的HTLV-I感染T细胞存活的因素。
