ER Proteins Effect on Class I MHC Assembly

描述（由申请人提供）：肽的MHC呈递具有广泛的重要性，正如受MHC分子影响的一系列疾病所示，例如感染、肿瘤、移植排斥和自身免疫。细胞表面主要组织相容性复合体（MHC）I类分子将肿瘤或病原体特异性肽呈递给T细胞，T细胞通过溶解恶性或感染的细胞作出反应。自体-MHC I类/肽复合物对于宿主的溶细胞性T淋巴细胞库的初级选择是必需的。此外，靶细胞上的表面MHC I类分子的数量影响它们被自然杀伤细胞识别。由于所有这些原因，携带肽的MHC I类分子的细胞表面表达具有免疫学重要性。在流出到细胞表面之前，MHC I类分子在内质网中的蛋白质复合物内接收肽。在肽加载复合物中，蛋白质钙网蛋白与MHC I类重链结合，并且其在复合物中的存在被tapasin上调。Tapasin与MHC I类重链结合，募集ERp 57和与抗原加工相关的转运蛋白（TAP），并稳定TAP。虽然tapasin作为一个关键因素，在控制MHC I类表面表达和肽的介绍，它调节MHC I类组装的机制知之甚少。 一个更完整的理解的重要性，MHC I类肽加载复杂的相互作用，涉及塔帕辛将有助于创建策略，影响肽的介绍，用于许多治疗目的。本项目的目的是确定由MHC I类分子调节抗原呈递的机制。我们的中心假设是，tapasin与其他组装复合物蛋白质的特异性相互作用调节MHC I类结合肽的序列和亲和力，MHC I类/p2 m异源二聚体的稳定性，最终肽结合之前，并最终细胞毒性T淋巴细胞的选择和反应。我们提出这些目标：1）确定肽加载复合物相互作用在稳定完整MHC分子和调节MHC I类肽库中的作用，2）确定组装复合物相互作用对开放MHC I类/p2 m异二聚体稳定性的影响，和3）表征肽加载复合物相互作用对T细胞识别、应答和发育的影响，使用体外和体内系统。在这个项目的完成，这是我们的期望，我们将有明确的贡献的肽加载复合物涉及tapasin的调节MHC I类结合肽库，MHC I类稳定，和T细胞功能。

DESCRIPTION (provided by applicant): MHC presentation of peptide has broad importance, as shown by the range of disease conditions influenced by MHC molecules, e.g. infections, tumors, transplantation rejection, and autoimmunity. Cell surface major histocompatibility complex (MHC) class I molecules present tumor- or pathogen-specific peptides to T cells, which respond by lysing malignant or infected cells. Self-MHC class I/peptide complexes are required for the primary selection of the host's repertoire of cytolytic T lymphocytes. In addition, the number of surface MHC class I molecules on target cells influences their recognition by natural killer cells. For all these reasons, cell surface expression of peptide-bearing MHC class I molecules is of immunological importance. Before egress to the cell surface, MHC class I molecules receive peptides within a complex of proteins in the endoplasmic reticulum. In the peptide-loading complex, the protein calreticulin binds to the MHC class I heavy chain, and its presence in the complex is up-regulated by tapasin. Tapasin binds to the MHC class I heavy chain, recruits ERp57 and the transporter associated with antigen processing (TAP), and stabilizes TAP. Although tapasin serves as a critical factor in the control of MHC class I surface expression and peptide presentation, the mechanisms whereby it regulates MHC class I assembly are poorly understood. A more complete understanding of the importance of MHC class I peptide-loading complex interactions involving tapasin would contribute to the creation of strategies to influence peptide presentation for many therapeutic purposes. The objective of this project is to define the mechanisms by which antigen presentation by MHC class I molecules is regulated. Our central hypothesis is that specific interactions of tapasin with other assembly complex proteins regulate the sequence and affinity of MHC class I-binding peptides, the stability of MHC class I/p2m heterodimers prior to final peptide binding, and ultimately cytotoxic T lymphocyte selection and response. We propose these Aims: 1) to determine the role of peptide-loading complex interactions in the stabilization of complete MHC molecules and in the regulation of the MHC class I peptide repertoire, 2) to define the effect of assembly complex interactions on the stability of open MHC class I/p2m heterodimers, and 3) to characterize the impact of peptide-loading complex interactions on T cell recognition, response, and development, using in vitro and in vivo systems. At the completion of this project, it is our expectation that we will have defined contributions of the peptide-loading complex involving tapasin to the regulation of the MHC class I-binding peptide repertoire, MHC class I stabilization, and T cell function.