Quality Control of MHC Class I Restricted Antigen Processing

MHC I 类限制性抗原加工的质量控制

基本信息

批准号：
9175668
负责人：
PETER CRESSWELL
金额：
$ 45.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175668
关键词：
Affinity Antigen-Presenting Cells Antigens Autoimmunity Binding Biochemical Biological CD8B1 gene Cells Complex Cross Presentation Cytosol Dendritic Cells Disulfides ERp57 Endoplasmic Reticulum Ensure Enzymes Generations Glucose Glycoproteins Goals Histocompatibility Antigens Class I Homologous Gene I-antigen Immune In Vitro Infection Lead Lectin Link MHC Class I Genes Malignant Neoplasms Mediating Molecular Chaperones Oxidoreductase Pathway interactions Peptides Phagosomes Play Polysaccharides Process Protein Fragment Proteins Quality Control Reaction Role Signal Transduction Structure Sulfhydryl Compounds T cell response T-Lymphocyte Testing Transferase Translating Virus antigen processing antigenic peptide transporter calreticulin dimer fighting flexibility killings multicatalytic endopeptidase complex neoplastic cell pathogen peptide I protein complex tapasin tumor

项目摘要

Project Summary MHC class I-restricted antigen processing is essential for making CD8+ T cell responses. It must function correctly for effective immune recognition of pathogens, and aberrations can lead to autoimmunity. The overall aim of this proposal is to understand the quality control processes regulating MHC class I- restricted antigen processing of conventional antigens, translated in the cytosol, and of exogenous antigens internalized by cross-presenting cells. The latter process is particularly poorly characterized, yet it is essential for priming CD8+ T cell responses. We wish to understand how these two different processing mechanisms drive the assembly of essentially the same pool of MHC-I peptide complexes. A critical quality control process in the endoplasmic reticulum (ER) that remains ill understood is the action of the enzyme UDP-glucose glycoprotein transferase (UGT1), which produces the correct monoglucosylated glycan structure that allows MHC-I molecules to maintain an interaction with the Peptide Loading Complex (PLC) via the lectin chaperone calreticulin, facilitating tapasin-mediated peptide exchange. This promotes the expression by the cell of complexes of MHC-I with peptides of high affinity. We will test the hypothesis that structural flexibility in the MHC-I peptide binding domain serves as a recognition signal for UGT1. A second component, which is found in both the ER and the endocytic pathway, is the tapasin homologue TAPBPR. In vitro, TAPBPR can induce peptide exchange by MHC-I molecules outside of the PLC, and it has also been shown to interact with UGT1. A second major goal is to determine whether TAPBPR mediates peptide exchange by MHC class I molecules in intact cells, whether this can occur both in the ER and the phagosomes of cross-presenting cells, and whether in either of these intracellular compartments the simultaneous interaction of TAPBPR with UGT1 focuses the enzymatic activity of UGT1 onto MHC-I molecules associated with low affinity peptides, facilitating their exchange for optimal peptides. The final goal is to determine how cross-presented intact antigens encounter proteasomes, which are essential for both conventional MHC-I antigen processing and cross- presentation. We have evidence that this interaction occurs proximal to, and probably within, phagosomes of cross-presenting cells. The mechanisms that regulate this interaction at both the cell biological and biochemical level will be investigated.

项目概要 MHC I 类限制性抗原加工对于 CD8+ T 细胞反应至关重要。它必须发挥作用正确地对病原体进行有效的免疫识别，而畸变会导致自身免疫。这该提案的总体目标是了解调节 MHC I 类的质量控制流程传统抗原的限制性抗原加工，在细胞质中翻译，以及外源性抗原抗原被交叉呈递细胞内化。后一个过程的特征特别差，但它对于启动 CD8+ T 细胞反应至关重要。我们希望了解这两种不同的加工机制驱动基本上相同的 MHC-I 肽复合物库的组装。一个内质网 (ER) 中的关键质量控制过程仍不清楚的是 UDP-葡萄糖糖蛋白转移酶 (UGT1) 的酶，它产生正确的单糖基化聚糖结构，允许 MHC-I 分子保持与通过凝集素伴侣钙网蛋白的肽加载复合物 (PLC)，促进 tapasin 介导肽交换。这促进了细胞表达 MHC-I 与高肽的复合物亲和力。我们将检验 MHC-I 肽结合域的结构灵活性的假设作为 UGT1 的识别信号。第二种成分，存在于内质网和内吞细胞中途径，是 tapasin 同源物 TAPBPR。在体外，TAPBPR 可诱导 MHC-I 进行肽交换 PLC 外部的分子，并且它也被证明与 UGT1 相互作用。第二个主要目标是确定 TAPBPR 是否介导完整细胞中 MHC I 类分子的肽交换，这是否可以同时发生在交叉呈递细胞的内质网和吞噬体中，以及是否发生在这些细胞内区室中的任何一个都集中了 TAPBPR 与 UGT1 的同时相互作用 UGT1 对与低亲和力肽相关的 MHC-I 分子的酶活性，促进它们交换最佳肽。最终目标是确定完整抗原如何交叉呈递遇到蛋白酶体，这对于传统的 MHC-I 抗原加工和交叉抗原处理都是必需的。推介会。我们有证据表明这种相互作用发生在附近，并且可能发生在内部交叉呈递细胞的吞噬体。细胞和细胞中调节这种相互作用的机制将研究生物学和生化水平。