抗体Fc受体相关基因Fcer1g在肠道ILC3s分化和功能中的调控作用及机制研究

Dysfunction of intestinal immune system often lead to diseases such as inflammatory bowel disease (IBD), which result in long-term morbidity and has become a global health problem. Type III innate lymphoid cells (ILC3s) are a new class of non-B and non-T lymphocytes that play critical roles in intestinal immunity and IBD. Because of lacking antigen receptor expression, how ILC3s sense immunological signals to specifically participate in an immune response is unclear. Through analyzing an intestinal immune cell atlas built in the lab, we found that intestinal ILC3s highly express Fcer1g gene, which is a common subunit of multiple different Fc receptors. There is no functional study of Fcer1g and Fc receptor-mediated signals in ILC3s reported. By genetic perturbation of Fcer1g gene in ILC3s specifically, our preliminary data demonstrated that Fcer1g gene promotes the differentiation of intestinal ILC3s at the steady state. Thus we hypothesize that Fcer1g gene-mediated antibody Fc receptor signaling may promote the differentiation and activity of ILC3s, thereby severing as an environment-sensing pathway. This study aims to (1) explore the function of Fcer1g gene in intestinal ILC3s in homeostatic and inflammatory conditions, (2) determine the effect of Fcer1g gene-mediated antibody Fc receptor signaling in ILC3s, and (3) dissect the molecular mechanism of Fcer1g in regulating ILC3s differentiation and function. If successfully executed, our study will fill the research gaps about ILC3s, and provide potential new targets for the treatment of IBD and other intestinal inflammatory diseases.

肠道免疫系统功能紊乱会导致炎症性肠炎等肠道疾病，是人类健康的巨大威胁。III型固有淋巴细胞（ILC3s）是一类近期发现的新型免疫细胞，在肠道稳态维持和炎症反应中发挥重要功能。目前ILC3s感知周边环境信号进而调节免疫应答的机制尚不完全明确。通过分析前期工作建立的肠道免疫系统单细胞图谱，我们发现肠道ILC3s高表达抗体Fc受体的亚基Fcer1g基因。通过初步分析已构建的Fcer1g条件性敲除小鼠，我们发现Fcer1g的缺失显著减少了肠道ILC3s的比例。据此，我们提出假设：Fcer1g辅助ILC3s感知免疫微环境，进而调节了ILC3s的分化和功能。本课题拟在肠道稳态和炎症状态下，探究Fcer1g在ILC3s中的功能；确定抗体Fc信号对ILC3s的效应；寻找Fcer1g调控ILC3s功能的分子机制。本课题可填补目前ILCs领域研究的相关空白，也可能为肠道炎症疾病治疗提供新的思路。

3型固有淋巴细胞（ILC3s）在调节粘膜稳态和炎症中发挥至关重要的作用，但ILC3s表型和功能的分子调控机制仍不完全清楚。在本项目中，我们发现ILC3s高表达的Fcer1g基因，该基因编码抗体Fc受体共用的γ链。Fcer1g的条件性敲除导致其结合伴侣分子（相互作用蛋白）缺失，而该伴侣分子是ILC3s中至关重要的细胞膜受体。丙氨酸扫描诱变（Alanine scanning mutagenesis）进一步显示，Fcer1g在转录后水平上稳定其伴侣，该功能依赖于第29位的天冬氨酸残基。Fcer1g在ILC3s中的表达确保了其对细菌和真菌感染的有效保护性免疫。在机制发明，我们发现，在应对感染时，Fcer1g介导的信号传导程序性支持ILC3s的转录状态和效应性细胞因子的产生。因此，我们的研究揭示了Fcer1g作为一种核心接头蛋白，稳定ILC3中的细胞膜表型分子的表达，并建立有效的抗感染免疫。