放射后小胶质细胞趋化CD8 T细胞介导迟发性脑损伤的机制研究

迟发性放射性脑坏死是头颈部肿瘤放疗后严重的并发症，临床上缺乏有效治疗手段。研究表明CD8 T细胞通过分泌细胞毒性因子参与了卒中等神经系统疾病的发生。我们前期通过对临床标本进行单细胞测序和免疫组化发现放射性脑坏死组织有明显的CD8 T细胞浸润，并且在动物模型中使用CD8 T细胞敲除的方式证明了CD8 T细胞具有加重放射性脑坏死的作用。CD8 T细胞的浸润由趋化作用介导，明确放射后何种趋化因子导致CD8 T细胞向脑组织募集对于阻止CD8 T细胞浸润，减轻放射性脑损伤具有重要作用。预实验结果发现放射后一类小胶质细胞分泌趋化因子CCL8，同时CD8 T细胞高表达CCL8的受体CCR5。本项目拟使用基因工程小鼠、小分子药物干预、双光子技术等手段探究 CD8 T细胞浸润脑组织的过程，明确小胶质细胞参与CD8 T细胞浸润脑组织的分子机制，为开发阻止CD8 T细胞浸润进而治疗放射性脑坏死的策略提供参考。

Delayed radiation-induced brain necrosis is a serious complication after radiotherapy for head and neck tumors, and there is a lack of effective clinical treatment. CD8 T cells participate in the occurrence of neurological diseases such as stroke by secreting cytotoxic factors. We performed single-cell sequencing and immunohistochemistry on clinical specimens and found that there was obvious CD8 T cell infiltration in radiation-induced necrosis tissue, and we used CD8 T cell depletion in animal models to prove that CD8 T cells aggravated radiation-induced brain necrosis. The infiltration of CD8 T cells is mediated by chemotaxis. It is important to clarify which chemokines cause CD8 T cell recruitment to brain tissue after radiation for making strategy preventing CD8 T cell infiltration and reducing brain damage. Our preliminary experimental results found that a subpopulation of microglia secreted the chemokine CCL8 after radiation, and CD8 T cells highly expressed CCL8 receptor CCR5. This project intends to apply genetic engineering mice, small molecule drug intervention, two-photon technology and other methods to explore the process of CD8 T cell infiltrating into brain tissue and clarify the molecular mechanism of microglia involved in CD8 T cell recruitment, which can provide references for the treatment development for radiation-induced brain necrosis targeting the prevention of CD8 T cell infiltrating into the brain tissue.