CD45+Ter119+CD71+细胞（CD45+EPC）介导CD8+T细胞对特异性抗原刺激耐受及机制研究

A group of CD45+EPC was discovered in the late stage of tumor progression, and it has strong immunosuppressive ability to CD8+T cells which cause CD8+T cell tolerance. However, the characteristics and molecular mechanisms of CD45+EPC leading to CD8+T cell tolerance are largely unknown. Based on previous studies and combined with relevant literature support, we proposed: CD45+EPC process and present antigen to CD8+ T cell. Afterwards, CD45+EPC release ROS, iNOS nitrify TCR-CD8 which cause the tolerance of CD8+T cell to specific antigen stimulation by reducing the ability of MHC-I to CD8+T cells. In this project, we establish different tumor-bearing models, adoptive transfer models to clarify the CD45+EPC-mediated CD8+T cell tolerance to specific antigen stimulation; Gene knockout mice and drug antibody blocking experiment was used to clarify the molecular mechanisms of CD45+EPC leading to CD8+T cell tolerance. Though this project, we could elucidate the causes of anti-tumor deficiency in clinical tumor patients. Moreover, it will provide new clues to the design of anti-tumor immunotherapy.

荷瘤晚期状态下机体存在一群CD45+EPC，这群细胞对CD8+T细胞具有极强的免疫抑制能力，造成CD8+T细胞耐受。然而CD45+EPC导致CD8+T细胞耐受的特点和具体分子机制尚未知晓。申请者基于前期研究发现并结合相关文献支持，提出科学假说：在晚期荷瘤情况下CD45+EPC加工并提呈抗原给CD8+T细胞，同时释放ROS,iNOS等硝化TCR-CD8，减低MHC-I与CD8+T细胞的结合能力，最终导致CD8+T细胞对特异性抗原刺激耐受。本项目拟通过建立不同的荷瘤模型，回输实验模型，明确CD45+EPC介导的CD8+T细胞对特异性抗原刺激耐受；利基因敲除小鼠和药物抗体阻断实验，阐明荷瘤状态下CD45+EPC介导CD8+T细胞对特异性抗原刺激耐受的具体分子机制。通过本项目的研究，有望深入理解临床晚期肿瘤患者免疫功能低下的具体原因，而且也将为肿瘤免疫治疗方案设计提供新思路。

荷瘤晚期状态下机体存在一群CD45+EPC，这群细胞对CD8+T细胞具有极强的免疫抑制能力，造成CD8+T细胞耐受。然而CD45+EPC导致CD8+T细胞耐受的特点和具体分子机制尚未知晓。申请者基于前期研究发现并结合相关文献支持，提出科学假说：在晚期荷瘤情况下CD45+EPC加工并提呈抗原给CD8+T细胞，同时释放ROS,iNOS等硝化TCR-CD8，减低MHC-I与CD8+T细胞的结合能力，最终导致CD8+T细胞对特异性抗原刺激耐受。本项目拟通过建立不同的荷瘤模型，回输实验模型，明确CD45+EPC介导的CD8+T细胞对特异性抗原刺激耐受；利用药物抗体阻断实验，阐明荷瘤状态下CD45+EPC介导CD8+T细胞对特异性抗原刺激耐受的具体分子机制。通过本项目的研究，有望深入理解临床晚期肿瘤患者免疫功能低下的具体原因，而且也将为肿瘤免疫治疗方案设计提供新思路。