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

摘要 这项研究的目标是检验胃肠道树突状细胞(DC)的假设 肠道通过Fc-epsilon-RI-IgE介导的肠腔抗原摄取，从而影响肠道 炎症反应和I型超敏反应。Fc-epsilon-RI是一种高亲和力的IgE Fc受体。 多聚体免疫识别受体，通过其阿尔法链上的单价表位与IgE结合。 抗原诱导的IgE-Fc-epsilon-RI复合体的交联通过信号亚单位引起细胞激活 受体(Fc-epsilon-RI-beta和常见伽马链的二聚体)的结合。FC-epsilon的一个独特功能- RI是其细胞类型和物种特异性的表达模式。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四聚体(α、β和两条伽马链)。在人类中，Fc-epsilon-RI 在肥大细胞和嗜碱性粒细胞上作为异四聚体组装，但另外也作为缺乏 β亚基。独特的是，人的Fc-epsilon-RI的异三聚体形式在抗原提呈时表达 细胞，包括肠道中的树突状细胞。受体的表面表达与过敏性疾病相关，并且 控制过敏反应过程中由IgE介导的细胞激活。与其他多聚体免疫识别不同 受体，表面表达是在亚单位的共翻译组装水平上调节的 内质网；但其调节机制尚不清楚。目标1将阐明结构 单个Fc-epsilon-RI亚基的特征决定了受体的组装，从而决定了Fcepsilon的表面表达- RI复合体。目标2将确定人三聚体Fc-epsilon-RI是否在DC上起作用或 巨噬细胞通过IgE介导的摄取途径提呈抗原。这套实验将使用Fcepsilon- 表达RI的小鼠细胞，使我们能够研究受体介导的功能后果 MHC II类和MHC I类途径中T细胞激活的抗原提呈。目标3将 有条件转基因动物体内研究IgE介导的肠道免疫应答 人Fc-epsilon-RIα链在DC上的表达

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.