Trefoil Factors Regulate Th2 Immunity

描述(由申请人提供)：2型免疫的特征是产生白介素4、5、13、25和IL-33，免疫球蛋白E(IgE)嗜酸性粒细胞增多，肥大细胞增多，嗜碱性细胞增多，交替激活的巨噬细胞(AAM)，平滑肌过度收缩，以及激活的杯状细胞产生粘液过多。驱动2型免疫的CD4+T辅助2细胞(TH2)对于抵御寄生虫的宿主保护至关重要，寄生虫在全球20多亿人中导致显著的发病率和死亡率。Th2细胞也是影响全球1亿多人的过敏性疾病和哮喘的主要驱动因素。然而，在体内启动TH2发育的分子机制仍然不清楚，也是许多科学争论的主题。在这里，我们提供了三叶因子2(TFF2)的证据，TFF2是一种粘液稳定蛋白，已知可以修复受损的上皮细胞，是启动TH2细胞和发展2型免疫的核心。钩虫感染可迅速诱导肺上皮细胞产生TFF2，使产生IL-33的树突状细胞和巨噬细胞聚集到引流淋巴结。TFF2可能通过CXCR4(可能的TFF2受体)募集巨噬细胞，但尚不清楚CXCR4是否是TFF2功能所必需的(S)。经TFF2处理的巨噬细胞通过依赖IL-33但不依赖MyD88的机制选择性地从NAOVE前体细胞扩增TH2细胞。目前尚不清楚巨噬细胞是否是TFF2驱动的TH2免疫所必需的。TFF2基因缺陷的小鼠对钩虫和多回钩虫分别产生受损的初级和记忆反应，这证明了该分子在2型免疫中的关键作用。然而，目前尚不清楚TFF2是否仅通过IL-33依赖机制发挥作用。这个项目的目标是验证我们的中心假设：从上皮细胞产生三叶因子2，通过诱导巨噬细胞特异性地诱导IL-33，启动针对钩虫的TH2免疫。具体地说，这个项目将确定TFF2介导的2型免疫诱导：(1)是否完全依赖于巨噬细胞，或者也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素，(3)需要上皮或抗原提呈细胞中的CXCR4信号。成功完成这些目标将使人们更好地理解寄生虫感染期间2型免疫是如何产生的，这也与用于治疗过敏性疾病的治疗方法有关。

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.