干细胞标志物CD133的α2,3-唾液酸化在神经干细胞诱导T细胞免疫耐受中的作用和机制

随着干细胞越来越多地地用于临床疾病的治疗，干细胞如何避开病灶区的CD8+ T细胞等免疫细胞“军队”杀伤越来越引起关注。探索干细胞表面糖蛋白与免疫细胞表面凝集素结合的机制和意义有助于发现干细胞免疫逃逸的新机制。我们预实验发现：干细胞标志物CD133在神经干细胞中存在α2,3-唾液酸化；通过α2,3-唾液酸化，CD133能和调控免疫耐受的凝集素Siglec-9结合；CD133通过Siglec-9抑制CD8+ T细胞增殖和表达杀伤细胞的颗粒酶；组织损伤后释放的基质细胞衍生因子能增强CD133的α2,3-唾液酸化。我们由此假设：CD133与Siglec-9结合介导神经干细胞诱导T细胞免疫耐受。本项目将利用神经干细胞和免疫细胞共培养、小鼠损伤动物模型，研究CD133的α2,3-唾液酸与Siglec-9结合在神经干细胞诱导T细胞免疫耐受中的意义、机制，从糖生物学的角度阐明神经干细胞免疫耐受的分子机制。

Stem cells have been increasingly used for the treatment of many diseases. Elucidating the mechanism of stem cells immune tolerance not only helps to understand mechanisms of the crosstalk between stem cells and microenvironment, but also helps to improve stem cells immune escape in stem cells therapy. Lectins on cells surfaces mediate cells immune tolerance by interacting with glycan. The stem cells microenvironment includs surrounding blood vessels, immune cells, fibroblasts, inflammatory cells and the extracellular matrix (ECM). Uncovering the mechanism and function of interaction between lectin of immune cells and the glycans of stem cells membrane proteins help to eluciding the mechanism regulating stem cells immune tolerance. CD133/Prominin-1 has received considerable interests due to its widespread use as a marker of various normal and cancer stem cells. Increasing studies indicate that CD133 regulates stem cells self-renewal, differentiation, and thearpy resistance. Our unpublished data showed that CD133 could be α2,3-sialylated in neural stem cells. Furthermore, CD133 on neural stem cells could interact with Siglec-9 on CD8+ T cells depending on its α2,3-sialylation. CD133 inhibited the proliferation of activated CD8+ T cells through Siglec-9. Furthermore, CD133 reduced the expression of granzyme B in CD8+ T cells through Siglec-9. In this project, we intend to clarify the structure alteration of CD133 α2,3-sialylation during neural stem cells differentiation, and to search the glycosyltransferase responsible for CD133 α2,3-sialylation. Furthermore, we perform to use neural stem cells and animal models to explore the function and mechanisms of the interaction between CD133 and Siglec-9 in neural stem cells inducing T cells immune tolerance. Through these efforts, we hope to illuminate the mechanism and function of CD133-Siglectin-9-SHP signaling axis in CD8+ T cells immune tolerance induced by neural stem cells.