TIPE2介导NK细胞肝脏免疫耐受的机制研究

Liver is an organ with predominant innate immunity, where large numbers of NK cells reside. Breakdown of NK cell immune tolerance was reported to be one of the key mechanisms in acute hepatic immune injury models, suggesting that negative regulation of NK cells should be critical for maintenance of homeostasis and normal physiological function of the liver. Lipid second messenger binding protein, TIPE2, was reported to protect against systemic autoimmunity mediated by TCR and TLR signaling, and to protect against liver injury. We observed high expression of TIPE2 in NK cells and plan to intensively investigate the regulatory function of TIPE2 in hepatic NK cells, the underlying molecular mechanisms and the related pathological impacts on hepatic innate immune responses. We plan to compare the expression of TIPE2 in NK cells along the development process among different organs, shedding light on its specific role in hepatic NK cells; and to assess the role of TIPE2 on NK cell development, NK cell effector function and hepatic immune responses; and to explore the underlying molecular mechanisms of TIPE2-mediated negative regulation of hepatic NK cells. The applicant has intensively studied the negatively regulatory role of inhibitory receptor TIGIT on NK cells in acute hepatic immune injury （Hepatology 2014a）and liver regeneration（Hepatology 2014b）, and therefore is well-prepared and capable of performing the current research.

肝脏是富集NK细胞的天然免疫优势器官。在肝脏急性免疫损伤模型中已经证实NK细胞免疫耐受被打破是关键机制之一，提示NK细胞的负相调控对于维持肝脏稳态以行使正常生理功能至关重要。已知脂质第二信号结合蛋白TIPE2可以负调TCR及TLR信号介导的自身免疫病变，并对肝脏损伤具有保护作用。我们初步发现TIPE2在NK细胞上高表达，拟深入研究TIPE2对肝脏NK细胞的负相调控功能、分子机制及其在肝脏天然免疫应答中的病理意义。拟比较TIPE2分子在不同脏器NK细胞发育中的表达，展示对肝脏NK细胞的特殊作用；研究TIPE2对NK细胞发育、功能及肝脏免疫应答的作用；研究TIPE2对肝脏NK细胞发挥负调作用的分子机制。申请人曾较深入研究了抑制性受体TIGIT在肝脏急性免疫损伤（Hepatology 2014a）和肝脏再生(Hepatology 2014b)中对NK细胞的负调作用，有较好基础和能力完成该研究。

TIPE2作为T细胞、巨噬细胞等的负调控因子已经有所报道，但TIPE2分子是否同为NK细胞的负调控因子、是否介导NK细胞对自身的耐受，目前尚不清楚。本研究探讨了TIPE2在NK细胞的表达水平，并揭示了TIPE2对NK细胞功能的影响及其潜在机制：在急性炎症过程中，TIPE2虽然并不显著影响NK细胞的迁移能力，但负调控NK细胞产生细胞因子IFN-gamma的能力；另一方面，TIPE2在肿瘤浸润NK细胞上表达，并拮抗NK细胞的免疫耗竭过程，限制免疫检验点分子的表达及多种耗竭标志的表达水平，对NK细胞介导的抗肿瘤免疫应答起正向调控作用，并在肿瘤模型中抑制肿瘤生长，而这一作用，可能与TIPE2分子介导的信号维持了T-bet分子在NK细胞中的表达、从而维持了NK细胞的效应功能有关系。本研究揭示了NK细胞的一个新型功能调节分子，为进一步阐释NK细胞的功能调节机制奠定了基础。