嗜中性粒细胞新亚群的鉴定及其在器官移植免疫应答中的作用

嗜中性粒细胞在炎性及免疫应答中发挥重要作用。现大家逐渐认识到嗜中性粒细胞不仅局限于传统的I 型和II型两亚群，可能具有更多的功能可塑性和极化类型。我们近来应用体外嗜中性粒细胞亚群诱导体系筛选发现，IL-23诱导嗜中性粒细胞分泌Th17类细胞因子谱；而IL-33诱导嗜中性粒细胞分泌Th2类细胞因子谱。该新亚群表现特有的表型特征、基因表达谱和生物功能。但嗜中性粒细胞新亚群的调控机制及其移植生物学意义尚待探讨。本项目将在前期工作基础上，利用心脏和皮肤移植小鼠模型、体外诱导体系及单细胞测序技术在体内外鉴定嗜中性粒细胞的异质性及新亚群，明确嗜中性粒细胞新亚群在器官移植免疫应答中的作用。凭借多种组学、基因编辑、分子生化、免疫学技术系统解析嗜中性粒细胞新亚群分化的重要分子调控网络。该项目的实施将有助于我们对嗜中性粒细胞功能可塑性和极化特征的认识，为明晰嗜中性粒细胞亚群在器官移植排斥中的作用提供新视角。

Neutrophils play critical role in innate and adaptive immune responses. It is gradually recognized that neutrophils are not restricted to type Ⅰneutrophils (N1) and type Ⅱneutrophils (N2) and neutrophils may have more functional plasticity and polarization type. Recently, we used the combinations of various cytokines to induce bone marrow derived neutrophils and found two new subsets of neutrophils: a subset of neutrophils induced by IL-23 express IL-17A, IL-17F and IL-22, whereas another subset of neutrophils induced by IL-33 express IL-4, IL-5, IL-9, and IL-13. Importantly, these cell subsets displayed distinctive phenotypes, gene expression profiles and bio-functions. However, but their molecular regulatory mechanism and biological function in immune response of organ transplantation need to be investigated. By using the in vitro neutrophil induction systems, heart or skin transplantation mouse models and single cell sequencing, we will identify new neutrophil subsets and clarify their roles in immune response of organ transplantation.By using bioinformatics, gene editing, molecular and biochemical, immunological technique we will recover the molecular regulation of new neutrophil subsets. Our study will clarify the functional polarizations of neutrophils, the molecular regulatory networks and their involvement in the immune response of organ transplantation, which may provide novel insights on the roles of different neutrophil subsets in the immune rejection and tolerance of transplanted organs.