高强度Fas活化信号抑制T细胞凋亡及相关机制研究

T cell immune response is finely tuned. One hand, bodies need to initiate effective T cell immune response to clear invading pathogens; on the other hand, the activated T cells need to be eliminated to avoid the damage of body caused by uncontrolled immune response. Programmed cell death mediated by Fas receptor is the critical mechanism to induce cell apoptosis. However, whether excessive T cells apoptosis wil cause inadequate immune response and impaire systematic immune defense? In our previous study, we found that high concentration of Fas-activated antibodies could inhibit apoptosis of Jurkat T cells, which is associated with the effect that high intensity of Fas signaling can increase TRIF expression. In addition, high intensity of Fas signaling could inhibit the amount of activated form of caspase-8. Therefore, we suppose that TRIF probably competitively combines with intracellular region of Fas receptor against caspase-8, inhibits activation of caspase-8 and subsequent decreases Fas induced T cell apoptosis. In this project, we will further confirm our hypothesis and unravel the underlying mechanism. The achievement of this project will reveal a novel mechanism about how T cells keep self-survival and sustain proper immune response to invading pathogens.

T细胞的免疫应答受着精细的控制。一方面在外界病原体入侵时，机体需要启动有效的T细胞应答，清除入侵的病原体；另一方面，机体需要及时清除活化的T细胞，避免过度应答对机体造成损伤。Fas受体介导的细胞程序性死亡是诱导活化T细胞凋亡的主要机制。但Fas诱导的T细胞过度凋亡是否可导致T细胞应答不足，削弱机体的免疫防御？我们前期实验发现，高浓度Fas活化抗体能抑制Jurkat T细胞的凋亡。而这一作用与高强度的Fas信号能上调TRIF表达相关。同时，高强度的Fas信号能抑制Jurkat T细胞中活化的caspase-8水平。因此，我们推测TRIF可能与caspase-8竞争性结合到Fas胞内段，抑制caspase-8活化，从而减少Fas诱导的T细胞凋亡。本项目将进一步验证我们这一科学假设并对相关机制进行深入探讨。我们的研究成果将揭示活化T细胞如何有效保持自身存活，从而维持机体适度免疫反应的新机制。

Fas受体，又叫CD95，是死亡受体家族最主要的成员之一。当与其天然配体FasL相互作用之后，启动细胞的死亡信号。在外来病原微生物特异性抗原引起的T细胞持续活化的过程中，活化的效应T细胞一方面介导对病原微生物的清除，另一方面可同时上调Fas和FasL的表达水平，增强对Fas诱导的凋亡的敏感性，抑制T细胞的过度活化。然而，Fas信号引起的细胞过度凋亡，也有可能导致效应T细胞的活化不足，从而无法有效清除入侵的病原微生物，削弱机体的防御体系。因此，机体同样可能通过某种机制去负向调控过度Fas信号引起的细胞凋亡。我们的研究结果发现，高强度Fas活化信号通过上调TRIF抑制Jurkat T细胞的凋亡，TRIF与caspase-8竞争性结合到DISC，从而抑制caspase-8的剪切与活化，并且高强度Fas活化信号通过抑制Syk激酶磷酸化来调节TRIF的泛素化降解。Fas信号引起的细胞过度凋亡，导致了效应T细胞的活化不足，从而削弱机体抵抗外来病原微生物入侵的能力，然通过本课题的研究，我们揭示了活化T细胞如何保持自身存活，从而维持机体适度免疫反应的新机制。