树突细胞MST1激酶对T细胞分化的调控效应及机制

Dendritic cells (DCs) bridge innate and adaptive immunity, but how DC-derived signals regulate T cell lineage choices remains unclear. MST1 signaling plays a great role in cell migration, survival and tumorigenesis. From our recent work, deletion of MST1 in DCs potentiated from TH17 cell-mediated autoimmune neuroinflammation, but deletion of TSC1 in macrophages or T cell did not. We also found that MST1 orchesrated the expression of cytokines and costimulatory molecules in DSs and further promote its maturation and antigen presenting capacity. Moreover, deletion of MST1 in DCs promote TH17 development and differentiation, not regulatory T cells (Treg cells). These indicate MST1 probably take important effects in balancing innate immunity and adaptive immunity. This study should use the DC specfic deletion mice and cellular molecular immunological technologies to identify MST1 signaling as a central pathway for the integration of instructive signals in DCs for T cell lineage differentiation and immunity, which should contribute to deeply understand the key mechanisms of innate cell-mediated programming of T cell lineage development, differentiation and immunoinflammation.

在机体免疫应答中，树突细胞（dendritic cells, DC）常通过指导T细胞分化而在免疫相关疾病中发挥重要调控作用。然而DC依赖性T细胞分化的调控机理目前仍不清楚。激酶MST1信号在细胞存活、增殖以及肿瘤发生中发挥重要调节作用。前期工作显示，MST1基因DC特异性剔除小鼠(MST1ΔDC)出现自身免疫表型，肠道淋巴组织TH17浸润增加，而TH1细胞变化不明显。MST1ΔDC小鼠也容易诱导自身免疫性神经炎症(EAE)。而且，MST1ΔDC小鼠DC促炎因子分泌增多及抗原提呈能力增强。体内、外实验显示，MST1ΔDC小鼠DC促进TH17分化，但不影响调节性T细胞产生。这提示，MST1信号很可能在平衡天然免疫和适应性免疫调节中发挥调节作用。本研究将应用 MST1ΔDC小鼠及细胞分子免疫学技术，解析DC特异性MST1缺失对CD4+T细胞亚群发育分化及免疫功能的调节作用，并初步阐明其分子机理。

在机体免疫应答中，树突细胞（dendritic cells, DC）常通过指导T细胞分化而在免疫相关疾病中发挥重要调控作用。然而DC依赖性T细胞分化的调控机理目前仍不清楚。激酶MST1信号在细胞存活、增殖以及肿瘤发生中发挥重要调节作用。课题研究发现，树突细胞激酶MST1缺失明显特异性促进Th17细胞分化并在自身免疫病（EAE）或真菌感染性炎症中发挥重要调控效应，该研究成果发表在Nature Communication, 2017。进一步，研究发现，激酶MST1在巨噬细胞功能分化中发挥调控作用。MST1缺失明显促进M1巨噬细胞分化在抗细菌感染中发挥重要调控作用。其机制主要与糖酵解代谢信号明显相关联，该部分结果在总结发表中。也证实，激酶MST1对中性粒细胞发育分化发挥调控作用。激酶MST1缺失影响粒巨细胞前体（GMP）的百分率和细胞数。进一步研究揭示主要是影响GMP到成熟中性粒细胞发育分化，而影响粒细胞发生过程。这部分结果在总结发表中。以上结果为MST1信号在平衡天然免疫和适应性免疫调节中的作用研究提供新证据。本研究为深入阐明Th17分化调控机制研究提供新机制，同时也为靶向Th17分化干预治疗自身免疫性疾病及真菌性感染等提供实验依据。