Trefoil Factors Regulate Th2 Immunity

描述（由申请人提供）：2型免疫的特征在于产生白细胞介素（IL）4、5、13、25和IL-33，免疫球蛋白E（IgE）嗜酸性粒细胞增多症，肥大细胞增多症，嗜碱性粒细胞增多症，交替激活的巨噬细胞（AAM），平滑肌过度收缩性和活化杯状细胞的粘液过度产生。驱动2型免疫的CD 4 + T辅助2细胞（TH 2）对于保护宿主免受寄生蠕虫的侵害至关重要，寄生蠕虫在全球超过20亿人中导致显著的发病率和死亡率。TH 2细胞也是过敏性疾病和哮喘的主要驱动因素，影响全球1亿多人。然而，引发体内TH 2发展的分子机制仍不清楚，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（TFF 2），一种粘液稳定蛋白，已知修复受损的上皮细胞，是核心的TH 2细胞的启动和2型免疫的发展。钩虫感染迅速诱导肺上皮细胞的TFF 2，其作用是将产生白细胞介素（IL）-33的树突状细胞和巨噬细胞募集到引流淋巴结中。TFF 2可能通过CXCR 4（假定的TFF 2受体）募集巨噬细胞，但尚不清楚CXCR 4是否是TFF 2体内功能所必需的。TFF 2处理的巨噬细胞通过IL-33依赖性但MyD 88独立性机制选择性地从原始前体扩增TH 2细胞。目前尚不清楚巨噬细胞是否是TFF 2驱动的TH 2免疫所必需的。TFF 2缺陷小鼠产生受损的主要和记忆反应对钩虫Nippostrongylus brasiliensis和Heligmosomoides polygyrus，分别，这表明该分子在2型免疫的关键作用。然而，目前尚不清楚TFF 2是否仅通过IL-33依赖性机制发挥作用。 本项目的目的是检验我们的中心假设：三叶因子2从上皮细胞的生产启动TH 2免疫钩虫通过IL-33诱导特异性在巨噬细胞。具体而言，该项目将确定TFF 2介导的2型免疫诱导：（1）是否仅依赖于巨噬细胞或还需要树突细胞和嗜碱性粒细胞，（2）是否需要IL-33作为宿主保护的必要和充分的因子，以及（3）是否需要上皮细胞或抗原呈递细胞中的CXCR 4信号传导。这些目标的成功完成将使我们更好地了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有关。

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.