Tim-3是广泛表达于免疫细胞上的检查点分子，因其在T细胞上的高表达与感染性疾病的免疫耐受相关，被视为新一代的免疫治疗靶点。我们前期发现Tim-3抑制巨噬细胞上MHC-I的表达及抗原呈递功能，提示该分子的调控作用不限于T细胞，但其分子机制及意义尚不清楚。MHC-I在呈递抗原给CD8+T细胞，激发抗感染应答中发挥关键作用。为全面认识Tim-3抑制抗感染免疫应答的机制，本项目拟在前期研究基础上阐明：1）Tim-3抑制MHC-I表达及抗原呈递的分子机制；2）以胞内菌及病毒感染模型为研究对象，通过Tim-3转基因、Tim-3基因敲除及巨噬细胞特异性Tim-3敲除小鼠实验，体内阐明Tim-3抑制MHC-I的机制及其对抗原特异性CD8+T细胞活化及疾病进程的影响；3）明确利用Tim-3拮抗剂增强MHC-I表达及CD8+T细胞应答的可行性，最终为Tim-3在抗感染免疫领域的应用提供新的理论及实验依据。

Tim-3 is an immune checkpoint inhibitor widely expressed on immune cells. As overexpression of Tim-3 on T cells has been associated with infection tolerance, it is now considered as a new generation of therapeutic target. We find that Tim-3 inhibits the expression and the antigen presentation activity of MHC-I on macrophages, suggesting the inhibiting function of Tim-3 is not limited to T cells. However, the mechanisms by which Tim-3 inhibits MHC-I remain to be determined. MHC-I is the key molecule responsible for antigen presentation and for triggering CD8+T cell mediated anti-infection immunity. To fully understand the mechanisms and the significance of Tim-3 mediated inhibition on anti-infection immunity, we will:1) investigate the molecule mechanisms by which Tim-3 inhibits the expression and the antigen presentation activity of MHC-I on macrophages. 2) establish Listeria Monocytogenes (L.M) and VSV (Vesicular Stomatitis Virus) infection models using wild type, Tim-3 transgenic, Tim-3 knockout, Tim-3 macrophage specific knockout C57BL/6 mice respectively, and try to find the roles of Tim-3 in suppressing MHC-I and in suppressing MHC-I mediated CD8+T cell response against infection in vivo. 3) investigate whether Tim-3 antagonist antibody can be used to reverse Tim-3 mediated suppression on MHC-I expression, antigen presentation and on CD8+T cells response against infection in vivo, hoping to find new strategies against infectious diseases.