Studies on Fc-epsilon-RI as an antigen presentation structure at mucosal surfaces

摘要 本研究的目的是验证胃肠树突状细胞（DCs） 道通过Fc-γ-RI-IgE介导的摄取处理腔内抗原，从而影响肠道 炎症反应和I型超敏反应。Fc-γ-RI，高亲和力IgE Fc受体，是一种免疫调节剂。 多聚体免疫识别受体，其通过其α链中的单价表位结合IgE。 抗原诱导的IgE-Fc-ε-RI复合物交联通过信号亚基引起细胞活化 受体（Fc-γ-RI-β和共同γ链的二聚体）。Fc-γ的一个独特特征是， RI是其细胞类型和物种特异性表达模式。在小鼠中，该受体仅表达为 肥大细胞和嗜碱性粒细胞上的异源四聚体（α、β和两个γ链）。在人类中，Fc-γ-RI 在肥大细胞和嗜碱性粒细胞上作为异源四聚体组装，但另外也作为缺乏 β亚基独特的是，人异源三聚体形式的Fc-γ-RI在抗原呈递上表达， 细胞，包括肠道中的DC。受体的表面表达与过敏性疾病相关， 控制过敏反应期间IgE介导的细胞活化。与其他多聚体免疫识别不同 受体，表面表达在亚基的共翻译组装水平上调节， 内质网;但调节机制仍不清楚。目标1将阐明结构 决定受体组装的单个Fc-RI-RI亚基的特征，从而决定Fceptide的表面表达。 RI复合物。目的2将确定人三聚体Fc-γ-RI是否在DC上起作用， 巨噬细胞通过IgE介导的摄取途径呈递抗原。这组实验将使用Fceptide- 表达RI的鼠细胞，使我们能够研究受体介导的 在MHC II类和MHC I类途径中用于T细胞活化的抗原呈递。目标3将 利用条件性转基因动物研究IgE介导体内肠道免疫应答 在DC上表达人Fc α-链-RI。

Abstract The goal of this research program is to test the hypothesis that dendritic cells (DCs) of the gastro intestinal tract process lumenal antigens by Fc-epsilon-RI-IgE mediated uptake, thereby affecting the intestinal inflammatory response and type I hypersensitivity. Fc-epsilon-RI, the high affinity IgE Fc-receptor, is a multimeric immune recognition receptor that binds IgE through a monovalent epitope in its alpha chain. Antigen-induced crosslinking of the IgE-Fc-epsilon-RI complex causes cell activation via the signaling subunits of the receptor (Fc-epsilon-RI-beta and a dimer of the common gamma chain). A unique feature of Fc-epsilon- RI is its cell type- and species-specific expression pattern. In mice, the receptor is expressed only as a heterotetramer (alpha, beta, and two gamma chains) on mast cells and basophils. In humans, Fc-epsilon-RI assembles as a heterotetramer on mast cells and basophils, but additionally also as a heterotrimer lacking the beta subunit. Uniquely, the human heterotrimeric form of Fc-epsilon-RI is expressed on antigen presenting cells, including DCs in the intestine. Surface expression of the receptor correlates with allergic diseases, and controls IgE-mediated cell activation during the allergic response. Unlike other multimeric immune recognition receptors, surface expression is regulated at the level of co-translational assembly of subunits in the endoplasmic reticulum; but the mechanism of regulation remains unknown. Aim 1 will elucidate structural features of individual Fc-epsilon-RI subunits that dictate receptor assembly and thus surface expression of Fcepsilon- RI complexes. Aim 2 will determine if the human trimeric Fc-epsilon-RI functions on DCs or macrophages to present antigen via IgE-mediated uptake pathways. This set of experiments will use Fcepsilon- RI-expressing murine cells that allow us to study functional consequences of receptor-mediated antigen presentation for T cell activation in the MHC class II and the MHC class I pathways. Aim 3 will investigate IgE-mediated intestinal immune responses in vivo using a transgenic animal conditionally expressing the human alpha-chain of Fc-epsilon-RI on DCs.