Trefoil Factors Regulate Th2 Immunity

描述（由申请人提供）：2型免疫的特征是白细胞介素（IL） 4、5、13、25和IL-33的产生，免疫球蛋白E （IgE）嗜酸性粒细胞增多，肥大细胞增多，嗜碱性粒细胞增多，可选活化的巨噬细胞（AAM），平滑肌过度收缩，以及活化的杯状细胞产生粘液过量。驱动2型免疫的CD4+ T辅助性2细胞（TH2）对于保护宿主免受寄生蠕虫的侵害至关重要。寄生蠕虫在全球20多亿人中造成严重的发病率和死亡率。TH2细胞也是过敏性疾病和哮喘的主要驱动因素，这影响到全世界1亿多人。然而，体内启动TH2发育的分子机制仍然不清楚，并且是许多科学争论的主题。在这里，我们提供的证据表明，三叶因子2 (TFF2)，一种已知修复受损上皮的粘液稳定蛋白，是TH2细胞启动和2型免疫发展的核心。钩虫感染可迅速诱导肺上皮的TFF2，其作用是招募产生白细胞介素(IL)-33的树突状细胞和巨噬细胞进入引流淋巴结。TFF2可能通过被推测为TFF2受体的CXCR4募集巨噬细胞，但目前尚不清楚CXCR4在体内是否为TFF2功能所必需。TFF2处理的巨噬细胞通过il -33依赖但不依赖myd88的机制，选择性地从原始前体扩增TH2细胞。目前尚不清楚巨噬细胞是否为tff2驱动的TH2免疫所必需。tff2缺陷小鼠对巴西尼波圆线虫和多回Heligmosomoides分别产生初级和记忆反应受损，这表明该分子在2型免疫中的重要作用。然而，尚不清楚TFF2是否仅通过依赖IL-33的机制发挥作用。本项目的目的是验证我们的中心假设：上皮细胞产生三叶因子2，通过IL-33在巨噬细胞中特异性诱导，启动针对钩虫的TH2免疫。具体而言，该项目将确定tff2介导的2型免疫诱导是否：(1)仅依赖巨噬细胞或还需要树突状细胞和嗜碱性细胞，(2)需要IL-33作为宿主保护的必要和充分因子，(3)需要上皮细胞或抗原呈递细胞中的CXCR4信号传导。成功完成这些目标将更好地理解寄生虫感染期间如何产生2型免疫，这也与用于治疗过敏性疾病的疗法相关。

DESCRIPTION (provided by applicant): Type 2 immunity is characterized by production of interleukins (IL's) 4, 5, 13, 25, and IL-33, immunoglobulin E (IgE) eosinophilia, mastocytosis, basophilia, alternatively activated macrophages (AAM), smooth muscle hypercontractility, and mucus overproduction from activated goblet cells. CD4+ T helper 2 cells (TH2) that drive Type 2 immunity are critical for host-protection against parasitic helminths that cause significant morbidity and mortality in more than 2 billion people world-wide. TH2 cells are also central drivers of allergic diseases and asthma, which affects more than 100 million people world-wide. However the molecular mechanisms that initiate TH2 development in vivo remain unclear and are topics of much scientific debate. Here, we provide evidence that Trefoil factor 2 (TFF2), a mucus-stabilizing protein known to repair damaged epithelia, is central to the initiation of TH2 cells and development of Type 2 immunity. Hookworm infection rapidly induces TFF2 from lung epithelia, which acts to recruit interleukin (IL)-33-producing dendritic cells and macrophages into draining lymph nodes. TFF2 may recruit macrophages through CXCR4, the putative TFF2 receptor, but it is unclear whether CXCR4 is necessary for TFF2 function(s) in vivo. TFF2- treated-macrophages selectively expand TH2 cells from naove precursors through an IL-33-dependent, but MyD88-independent mechanism. It is unknown whether macrophages are necessary for TFF2-driven TH2 immunity. TFF2-deficient mice generate impaired primary and memory responses against the hookworms Nippostrongylus brasiliensis and Heligmosomoides polygyrus, respectively, which demonstrate the crucial role of this molecule in Type 2 immunity. However, it is unclear whether TFF2 functions solely through IL-33 dependent mechanisms. The goal of this project is to test our central hypothesis that: Trefoil factor 2 production from epithelia initiates TH2 immunity against hookworms through IL-33 induction specifically in macrophages. Specifically, this project will determine whether TFF2-mediated induction of Type 2 immunity: (1) is solely dependent upon macrophages or also requires dendritic cells and basophils, (2) requires IL-33 as a necessary and sufficient factor for host-protection and (3) requires CXCR4 signaling in epithelia or antigen- presenting cells. Successful completion of these aims will produce a better understanding of how Type 2 immunity is generated during parasite infection, which also bears relevance to therapies used to treat allergic disease. PUBLIC HEALTH RELEVANCE: Rapid induction of pathogen-specific immunity can determine life vs. death. We have uncovered a novel mechanism that initiates Type 2 immunity, which is responsible for protection against parasitic helminth infections and most allergic responses. Collectively, these diseases affect billions of people worldwide. This project will generate a better understanding of the molecular mechanisms that initiate Type 2 immunity.