AML中免疫抑制受体介导的TCR Vβ T细胞克隆功能缺陷及其逆转调控

纠正和重建T 细胞免疫功能功是减少白血病复发和延长生存的关键因素之一，我们前期研究发现不同急性髓细胞白血病（AML）病人T细胞功能重建的差异性很大，可能与免疫抑制受体所介导的负调控相关。故在鉴定抗AML的T细胞克隆，上调T细胞受体（TCR）ζ信号通路而提高T细胞功能研究基础上，进一步分析AML病人TCR Vβ亚家族T细胞中免疫抑制受体（PD-1，CTLA-4，Tim-3，LAG-3和BTLA）的分布和表达特点，通过单相或多相靶向抑制不同免疫抑制受体、联合免疫刺激因子和转基因上调TCR信号等调控处理，分析AML病人CD4+和CD8+TCR Vβ亚家族T细胞增殖、活化和抗白血病功能改善情况，分析TCR下游信号通路（Akt、Lck和NFAT等）变化和明确其作用途径。最终，明确不同亚型和不同个体AML病人T细胞免疫缺陷及其逆转的差异性特点，为设计更精准的AML相关T细胞免疫治疗策略提供新的依据。

Inversion and reconstitution of T cell immunity is one of the key factor for reducing leukemia relapse and extending overall survival. Our previous studies found that the obvious difference of the T cell immune reconstitution from different acute myeloid leukemia (AML) patients, which is thought to be relating to the negative regulation of T-cell immunosuppressive receptors. Therefore, based on our previous findings on the identification of anti-AML T cell clones and enhancement of T cell immunity through upregulating T cell receptor (TCR) ζ signal pathway, the propose of the study is to further analyze the characteristics of distribution and expression of immunosuppressive receptors (PD-1, CTLA-4, Tim-3, LAG-3 and BTLA) in TCR Vβ subfamily T cells from AML patients, evaluate the improvement of proliferation, activation and anti-leukemia cytotoxicity of CD4+ and CD8+ TCR Vβ subfamily T cells by upregulating TCR signal pathway through single- or multi-agent target inhibition on immunosuppressive receptors, or combination with immune stimulator factors or gene transfection, characterize the change of TCR downstream signal pathway such as Akt, Lck and NFAT, and confirm the effect mechanism. Finally, the results will be expected to define the characteristics of the difference on T cell immune deficiency and its inversion in different subtypes and different individuals of AML, which will provide the new data for designing more precise T cell immunotherapy strategy for AML patients.