靶向TIGIT分子逆转泡球蚴感染导致的T细胞免疫耗竭及其机制

Alveolar echinococcosis (AE) is a rare, but dangerous zoonotic helminthic disease due to the proliferation of the larval stage of the cestode, Echinococcus (E.) multilocularis. In humans, the lesions behave like a slow-growing liver cancer, progressively invading the neighboring tissues and organs. The prognosis of AE patients is closely related to the immune state of the host. In our previous study, we found that the proportions of CD8+T cells were increased in liver lesions and peripheral of AE patients, but CD8+T cell’s function was decreased. The expression of the T cell co-inhibitory receptor TIGIT (T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) was up-regulated, and its ligand CD155 on the liver cell surface was highly expressed. It suggested that TIGIT/CD155 pathway regulates CD8+ T cell exhaustion, which caused by E. multilocularis infection, but the mechanism is unknown. Based on the scientific hypothesis “Targeting TIGIT molecule reverse CD8+ T cell exhaustion caused by E. multilocularis infection”, we plan to verify the role and clinical significance of TIGIT molecule in the CD8+ T cell exhaustion in AE patients, by using clinical specimens to detect the change of CD8+ T cells function, as well as expression and localization of TIGIT and CD155. Through the establishment of E. multilocularis infection in mice (wild type and TIGIT deficient type), we plan to identify CD8+ T cells phenotype and functional status, in vivo expression dynamics of TIGIT molecule, and their relationship with parasitic and liver damage, and elucidate the molecular mechanisms of TIGIT in CD8+ T cell exhaustion. Finally, we explore the feasibility and effectiveness for reversing CD8+ T cells function by blocking TIGIT molecules and adoptive transfer experiments, so as to provide a basis for further exploration of immunotherapy of hydatid disease.

泡型包虫病（AE）有虫癌之称，病人转归与免疫密切相关。我们前期发现AE病人肝脏病灶和外周CD8+ T细胞增多但功能降低，表面共抑制分子TIGIT表达上调，肝细胞表面配体CD155高表达，提示TIGIT/CD155通路参与泡球蚴感染所致CD8+ T细胞免疫耗竭，但机制不明。基于“靶向TIGIT分子逆转泡球蚴感染所致T细胞免疫耗竭”的科学假说，拟利用临床标本，检测CD8+ T细胞、TIGIT、CD155变化和定位，明确TIGIT在AE患者CD8+ T细胞免疫耗竭中的作用及临床意义。利用泡球蚴感染小鼠（野生型和TIGIT缺陷型），分析CD8+ T细胞和TIGIT分子体内表达动力学、表型与功能状态的动态变化及与寄生和肝损伤关系，阐明TIGIT在CD8+ T细胞免疫耗竭中的分子机制。通过阻断TIGIT分子和过继转输实验，确认靶向TIGIT逆转CD8+ T细胞功能的价值，为探索免疫治疗包虫病奠定基础。

泡型包虫病（AE）有虫癌之称，危害严重，病程与免疫密切相关。我们前期发现提示TIGIT/CD155通路参与泡球蚴感染所致CD8+T细胞免疫耗竭，但机制不明。本研究围绕“靶向TIGIT分子是否逆转泡球蚴感染所致T细胞免疫耗竭”这一科学问题展开，通过外周血和临床手术肝脏标本，研究AE患者外周血和肝脏区域募集 CD8+T和CD4+T细胞表面共刺激分子及其功能的变化，结果显示TIGIT表达的肝脏T细胞在AE患者中显著增强，并与病变活性呈正相关。在肝脏和外周血T细胞中高TIGIT的表达与其功能衰竭有关，其配体CD155在周围的肝细胞高表达。在泡球蚴感染小鼠中，观察到类似的TIGIT表达的肝脏T细胞功能衰竭和肝细胞上丰富的CD155表达。在人血T细胞和肝细胞HL-7702共培养实验中，CD155诱导TIGIT+T细胞功能损害，TIGIT抗体的体外阻断恢复了AE患者T细胞的功能。在体内阻断CD8+T 和CD4+T细胞可防止T细胞衰竭，抑制泡球蚴感染小鼠的疾病进展。清除CD8+T或CD4+T细胞后再给与抗TIGIT抗体结果提示抑制泡球蚴感染小鼠疾病进展中CD4+T细胞发挥重要作用，CD8+T细胞发挥次要作用。为免疫治疗包虫病寻找靶点奠定基础。

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