SLAM家族调节肺II型免疫反应的机制及应用研究

Type II immunity in the lung is mainly carried out by adaptive immune T helper 2 (TH2) cells and innate lymphoid cells (ILC2s). Currently, how the function of these cells in the lung are regulated by surface receptors is unknown. Seven members of Signaling Lymphocytic Activating Molecule (SLAM) family receptors were widely distributed on the surface of hematopoietic cells, and the deficiency of SLAM-Associated Protein (SAP), the downstream signaling molecule of SLAM family receptors, would lead to the impaired induction of TH2 immune response. Due to the serious redundancy among seven SLAM family members, whether these receptors regulate pulmonary type II immunity is unknown. Through the generation of combined 7 SLAM family receptor-deleted mice, we preliminarily found that SLAM and CD48, two members of the SLAM family, were crucial for TH2 cell differentiation and activation-induced T cell aggregation. The SLAM-family deficient mice were not sensitive to OVA-induced asthma. In addition, it was also found that adaptive immune cells in the lung, most likely T cells and B cells, suppressed the early differentiation and activation of ILC2 cells through the homotypic recognition mediated by SLAM family. This application is intended to further investigate the effect of SLAM-family deletion on TH2- and ILC2-mediated type II asthma responses, and to analyze the molecular mechanism. This study is expected to propose the concept of “lung-resident adaptive immune cells negatively modulate type II innate immune response through SLAM family receptors”. The results will reveal that SLAM family members differentially regulate the functions of TH2 and ILC2 cells. It is also expected to find potential receptors as a target for the treatment of asthma.

肺II型免疫主要是由获得性免疫TH2和天然免疫ILC2细胞介导，目前这些细胞在受体水平的功能调节机制不详。SLAM家族7个成员分布于造血细胞表面，其下游信号蛋白SAP缺失会导致TH2免疫反应下降。由于SLAM家族存在严重的冗余性，SLAM家族是否调节肺II型免疫未知。通过制备7个SLAM家族受体联合缺失小鼠，我们初步发现SLAM家族成员SLAM和CD48对TH2细胞分化和活化诱导的聚集至关重要，SLAM家族缺失小鼠对OVA诱导的哮喘不敏感；此外还发现获得性免疫细胞通过SLAM家族的同源识别抑制了ILC2细胞早期分化和活化。该申请拟进一步研究SLAM家族缺失对TH2和ILC2介导的II型哮喘反应的影响，并解析其分子机制。该研究有望提出“肺局部获得性免疫细胞通过SLAM家族受体负调II型免疫反应”这一概念；揭示SLAM家族成员差异性调控TH2和ILC2细胞功能；有望发现治疗哮喘的潜在受体靶点。

II型免疫主要是由获得性免疫TH2和天然免疫ILC2细胞介导，目前这些细胞在受体水平的功能调节机制不详。本课题旨在解析SLAM家族受体对TH2肺部炎症反应、ILC2发育、ILC2肺部炎症反应三方面的调节作用：首先，通过在SLAM家族受体联合缺失小鼠上构建OVA诱导的哮喘模型，发现TH2 诱发哮喘很大程度上依赖于SLAM家族受体。机制上，通过采用采用多种遗传学小鼠模型，我们发现SLAM家族受体成员1（SLAMF1）和SLAM家族受体成员2（SLAMF2）分别促进CD4+ T细胞的TH2极化和活化。该工作对哮喘治疗具有较好转化应用前景。第二，通过采用新构建的SLAM家族受体条件性敲除小鼠模型，发现适应性免疫细胞来源的SLAM家族受体可抑制ILC2发育。在ILCP向ILC2发育过程，SAP的表达快速丢失，导致SLAMF3/5转而招募磷酸酶而发挥抑制作用。本研究不仅揭示了ILC2发育分化阶段的负调机制，还一定程度上解释了ILC2主要聚集于非淋巴器官/组织的原因。最后，通过构建ILC2介导的肺炎模型，发现SLAM家族受体可以促进肺部炎症转归。机制上，肺部引流淋巴结T细胞来源的SLAMF3和SLAMF5可以抑制ILC2的IL-13生成，后者下调DC对TH2的促进作用，从而促进肺炎转归。本研究不仅揭示ILC2型哮喘的炎症衰退新机制，还首次揭示了ILC2在淋巴结的生物学功能。SFR调节TH2反应部分整理中。SFR调节ILC2发育及功能两部分整理好，待发表。