再生障碍性贫血调节T细胞功能缺陷的分子机制研究

Aplastic anemia (AA) was a life-threatening bone marrow failure. The core point of immunopathological mechanisms was immune-mediated destruction of bone marrow hematopoietic stem / progenitor cells (HSC/HPC) by activated effector T cells. Regulatory T cells (Treg) have powerful immunosupprssion potential on effector T cells dependent on stablity of trancriptional factor Foxp3 expression. Our previous work have demonstrated that impairment of Treg-mediated immunosuppression on effector T cells was intrinsic to Treg (Shi J, et al. Blood,2012), but little was known regarding the molecular mechanisms. Here, our further interesting focus on three key issues: aberrant expression of inhibitory molecules by Treg; the plasticity of Treg by reprogramming process leading to the generation of pathogenic Th1-like or Th17-like Treg; the molecular defects of Foxp3 expression under control of several key transcriptional factors, microRNAs, and DNA methylation of CpG island. To clarify the molecular defects of Treg dysfunction could contribute to boarden our knowledge of pathophysiology and provide powerful evidence for a Treg-oriented immunotherapy strategy in patients with AA.

再生障碍性贫血（AA）是一种严重威胁患者生命的骨髓衰竭性疾病，其病理机制的核心是活化的效应T细胞介导的骨髓造血干/祖细胞免疫损伤。调节T细胞（Treg）表达功能性转录因子Foxp3，对效应T细胞发挥重要的免疫抑制功能。我们前期研究发现Treg细胞内在缺陷导致免疫抑制效应T细胞的功能降低（Shi J et al. Blood, 2012），但其分子机制不明。我们拟继续的研究工作重点在3个层面展开：①Treg细胞膜效应分子表达异常；②Treg细胞具有免疫可塑性，可重编程后转换为病理性Th1、Th17样Treg细胞；③Foxp3基因表达受转录因子、microRNAs及CpG岛DNA甲基化调控的分子缺陷。阐明AA患者Treg细胞功能缺陷的分子机制这个关键科学问题，将丰富我们对AA免疫病理机制的认识，为探索基于Treg细胞的免疫治疗策略提供科学理论基础。

活化效应T细胞介导的造血干/祖细胞损伤是再生障碍性贫血（Aplastic anemia, AA）异常免疫病理机制的核心，而调节T细胞（regulatory T cell, Treg）内在功能缺陷对于发病不可或缺。我们研究发现，AA患者外周血各亚型Treg细胞比例均有不同程度的减低，以静息Treg更显著。此外，AA患者Treg细胞膜表面CD39、CD73表达增强，抑制效应T细胞代谢。体外刺激培养发现，AA患者CD4+T细胞有Th1细胞分化倾向，说明AA患者Treg细胞具有重编程能力。在此基础上，我们对AA患者外周血T细胞进行全转录组测序分析：我们发现，VSAA组CD4+T淋巴细胞差异基因表达与正常对照组趋势相反，而SAA组CD8+T淋巴细胞差异基因表达与正常相反。我们将进一步探索AA患者中异常CD4+/CD8+T淋巴细胞特异性靶基因，为进一步为AA分子免疫学治疗提供理论基础。