Supraoptimal peptide major histocompatibility complex causes a decrease in Bcl-2 levels and allows tumor necrosis factor α receptor II-mediated apoptosis of cytotoxic T lymphocytes
Supraoptimal peptide major histocompatibility complex causes a decrease in Bcl-2 levels and allows tumor necrosis factor α receptor II-mediated apoptosis of cytotoxic T lymphocytes
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DOI：
10.1084/jem.188.8.1391
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发表时间：
1998-10-19
影响因子：
15.3
通讯作者：
Berzofsky, JA
中科院分区：
文献类型：
--
作者：
Alexander-Miller, MA;Derby, MA;Berzofsky, JA
细胞毒性 T 淋巴细胞 (CTL) 是病毒清除的主要介质，但高病毒负荷可能导致抗原特异性 CTL 缺失。我们之前报道了这种缺失的潜在机制：肿瘤坏死因子（TNF）-α介导的细胞凋亡是由超最佳肽-主要组织相容性复合物刺激引起的。在这里，我们表明，尽管死亡是由 TNF-α 及其受体 (TNF-RII) 介导的，但令人惊讶的是 TNF-α 的抗原剂量依赖性都没有。 TNF-RII 的产生和表达都可以解释细胞凋亡的剂量依赖性。相反，我们发现了超最佳抗原在显着降低抗凋亡蛋白 Bcl-2 水平方面的先前未被认识到的作用，并且可能解释了通过 TNF-RII 维持死亡信号的敏感性或能力的增加。这种减少需要通过 TCR 发出信号，而不仅仅是通过 TNF-RII。尽管 TNF-RII 介导的死亡没有像 TNF-RI 介导的那样广泛研究，但我们在此表明，它也依赖于半胱天冬酶的蛋白水解切割，并由与抗原的短暂初次接触触发。这些结果表明，决定簇密度可以通过降低 Bcl-2 水平来改变 CTL 对 TNF-α 细胞凋亡作用的敏感性，从而调节免疫反应。
Cytotoxic T lymphocytes (CTLs) are primary mediators of viral clearance, but high viral burden can result in deletion of antigen-specific CTLs. We previously reported a potential mechanism for this deletion: tumor necrosis factor (TNF)-alpha-mediated apoptosis resulting from stimulation with supraoptimal peptide-major histocompatibility complex. Here, we show that although death is mediated by TNF-alpha and its receptor (TNF-RII), surprisingly neither the antigen dose dependence of TNF-alpha. production nor that of TNF-RII expression can account for the dose dependence of apoptosis. Rather, a previously unrecognized effect of supraoptimal antigen in markedly decreasing levels of the antiapoptotic protein Bcl-2 was discovered and is likely to account for the gain in susceptibility or competence to sustain the death signal through TNF-RII. This decrease requires a signal through the TCR, not just through TNF-RII. Although death mediated by TNF-RII is not as widely studied as that mediated by TNF-RI, we show here that it is also dependent on proteolytic cleavage by caspases and triggered by a brief initial encounter with antigen. These results suggest that determinant density can regulate the immune response by altering the sensitivity of CTLs to the apoptotic effects of TNF-alpha by decreasing Bcl-2 levels.