基于T细胞亚群分化与TLR2/TRAF6信号通路探讨ESAT-6抑制同种异体移植排斥的分子免疫机制

传统免疫抑制剂虽然可以抑制移植排斥反应，但长期使用副作用较大。最近研究表明，由结核杆菌分泌的一种蛋白ESAT-6能抑制T细胞活化。T细胞亚群在参与器官移植排斥和移植耐受中发挥着主导作用，移植排斥主要由Th1/Th17及其效应T细胞(Teff)介导，而调节性T细胞（Treg）则能抑制移植排斥反应并在诱导免疫耐受中起着关键作用。我们首次检测了ESAT-6对移植排斥的抑制效果，初步预实验结果证实，ESAT-6能显著抑制小鼠同种异体胰岛移植物的排斥，并能抑制T细胞的体外增殖与活化。因此，本项目将联合使用ESAT-6与其它免疫抑制剂例如雷帕霉素以诱导移植物的长期存活，进一步探索ESAT-6在移植排斥反应中对T细胞亚群（Th1/Th17/Teff与Treg）分化的影响，并基于TLR2/TRAF6信号通路深入研究其作用的分子免疫机制，为临床治疗器官移植排斥和诱导移植耐受提供实验依据。

Although conventional immunosuppressive agents can inhibit allograft rejection, their long-term utilization usually results in various side effects. Recent studies have shown that ESAT-6, a secretory protein produced Mycobacterium tuberculosis, can suppress T cell activation. As we know, T cell subsets play a major role in allograft rejection as well as transplant tolerance. Allograft rejection and autoimmune responses are mainly initiated and mediated by Th1/Th17 and Teff cells while regulatory T cells (Treg) can suppress allograft rejection and are critical for the induction of immune tolerance. In our preliminary studies, we tested the inhibitory effects of ESAT-6 on allograft rejection. Here we found that ESAT-6 indeed inhibited islet allograft rejection in mice. We also demonstrated that it suppressed T cell proliferation and activation in vitro. Based on these findings, we propose to induce long-term allograft survival by combining treatment of ESAT-6 with other immunosuppressive agents, such as rapamycin. Furthermore, we will study its impacts on differentiation of various T cell subsets, including Th1/Th17/Teff and Treg cells. Finally, we will explore the relevant molecular mechanisms underlying its immunoregulatory effects on TLR2/TRAF6 signaling. This study will provide novel experimental data that support clinical application of ESAT-6 for the suppression of transplant rejection or induction of transplantation tolerance.