Regulation of Antigen Presentation by APLP-2

描述（由申请人提供）：针对感染的细胞免疫反应是在肽装载和主要组织相容性复合体（MHC） I类分子的组装水平上启动的。MHC I类非自身肽的呈现会触发溶细胞T淋巴细胞杀死被感染的细胞。MHC I类重链与抗原肽和β -微球蛋白（β - 2m）的组装是通过与内质网（ER）蛋白（如钙连联蛋白、TAP、钙网蛋白、酶联蛋白和ERp57）结合而发生的。另一种细胞蛋白，淀粉样前体样蛋白2 (APLP-2)，最近被证明与MHC I类分子相关，我们的初步研究结果表明，APLP-2下调细胞表面MHC I类分子的数量。我们实验室的长期目标是了解MHC I类分子对抗原呈递的调控。本探索性/发展性研究（R21）拨款提案的目的是确定APLP-2对病原体源性表位呈递的影响。我们的中心假设是，APLP-2调节MHC I类成熟和病原体衍生肽的呈递，包括NIAID生物防御优先病原体（汉滩病毒、结核分枝杆菌、甲型流感、登革热病毒、日本脑炎病毒和单核细胞增生李斯特菌）的已知表位。从这项研究中获得的新见解将阐明APLP-2在调节MHC I类组装途径中的作用，并可能导致新的基于免疫的方法来预防或治疗感染。

DESCRIPTION (provided by applicant): The cellular immune response against infections is initiated at the level of peptide loading and assembly of major histocompatibility complex (MHC) class I molecules. MHC class I presentation of nonself peptides triggers killing of infected cells by cytolytic T lymphocytes. The assembly of the MHC class I heavy chain with antigenic peptide and beta2-microglobulin (Beta2m) occurs via association with endoplasmic reticulum (ER) proteins such as calnexin, TAP, calreticulin, tapasin, and ERp57. Another cellular protein, amyloid precursor-like protein 2 (APLP-2), has recently been shown to associate with MHC class I molecules, and our preliminary findings indicate that APLP-2 down regulates the quantity of MHC class I molecules at the cell surface. The long-range goal of our laboratory is to comprehend the regulation of antigen presentation by MHC class I molecules. The objective of this Exploratory/Developmental Research (R21) Grant proposal is to define the effect of APLP-2 on the presentation of pathogen-derived epitopes. Our central hypothesis is that APLP-2 regulates MHC class I maturation and presentation of pathogen-derived peptides, including known epitopes from NIAID biodefense priority pathogens (Hantaan virus, Mycobacterium tuberculosis, influenza A, dengue virus, Japanese encephalitis virus, and Listeria monocytogenes). New insights obtained from this study will clarify the role of APLP-2 in the regulation of the MHC class I assembly pathway and may lead to new immune-based means to prevent or treat infections. The Specific Aims of this proposal are: Aim 1. To ascertain the cellular location of interacting APLP-2/MHC class I molecules and the influence of APLP-2 on MHC class I presentation of peptide. We hypothesize that APLP-2 regulates MHC class l peptide presentation at a late stage in MHC class I maturation. Aim 2. To determine the effect of APLP-2 on T lymphocyte recognition of pathogen epitopes. We hypothesize that the presentation of epitopes from NIAID priority pathogens is affected by APLP-2 interaction with the MHC class I molecule.