ER Proteins Effect on Class I MHC Assembly

描述（由申请人提供）：MHC肽的表现具有广泛的重要性，正如MHC分子影响的疾病条件范围所示，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类分子向T细胞提供肿瘤或病原体特异性肽，T细胞通过裂解恶性或感染细胞作出反应。自体mhc I类/肽复合物是对宿主的细胞溶解性T淋巴细胞库进行初步选择所必需的。此外，靶细胞表面MHC I类分子的数量影响其被自然杀伤细胞识别。因此，携带多肽的MHC I类分子在细胞表面的表达具有重要的免疫学意义。在进入细胞表面之前，MHC I类分子在内质网的蛋白质复合体内接受肽。在肽负载复合体中，钙调蛋白与MHC I类重链结合，其在复合体中的存在被tapasin上调。Tapasin结合MHC I类重链，招募ERp57和与抗原加工相关的转运体（TAP），并稳定TAP。尽管tapasin是控制MHC I类表面表达和肽呈递的关键因素，但其调节MHC I类组装的机制尚不清楚。

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.