ER Proteins Effect on Class I MHC Assembly

描述(由申请人提供)：MHC分子影响的一系列疾病情况，如感染、肿瘤、移植排斥和自身免疫，表明MHC呈递具有广泛的重要性。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多肽呈递给T细胞，T细胞通过裂解恶性细胞或感染细胞来应答。自身MHC-I类/肽复合体对于宿主的溶细胞T淋巴细胞库的初步选择是必需的。此外，靶细胞表面MHC I类分子的数量影响自然杀伤细胞对它们的识别。因此，细胞表面含肽MHC-I类分子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中接收多肽。在多肽负载复合体中，钙网蛋白与MHC I类重链结合，其在复合体中的存在受到Tapasin的上调。Tapasin与MHC I类重链结合，招募ERp57和与抗原处理相关的转运体(TAP)，并稳定TAP。尽管Tapasin在控制MHC-I类分子的表面表达和多肽递呈中起关键作用，但其调控MHC-I类分子组装的机制却知之甚少。 更全面地了解涉及Tapasin的MHC-I类多肽负载复合体相互作用的重要性，将有助于创建影响多肽呈递的策略，以达到许多治疗目的。这个项目的目标是确定MHC I类分子的抗原呈递受到调控的机制。我们的中心假设是，Tapasin与其他组装复合体蛋白的特异性相互作用调节MHC I类结合多肽的序列和亲和力，调节MHC I类/p2m异源二聚体在最终结合多肽之前的稳定性，并最终调节细胞毒性T淋巴细胞的选择和反应。我们提出的目标是：1)确定多肽负载复合体相互作用在稳定完整的MHC分子和调节MHC I类多肽谱系中的作用；2)确定组装复合体相互作用对开放的MHC I/p2m类异源二聚体稳定性的影响；3)利用体外和体内系统表征多肽负载复合体相互作用对T细胞识别、反应和发育的影响。在这个项目完成时，我们期望我们将确定涉及Tapasin的多肽负载复合体对MHC I类结合多肽库的调节、MHC I类稳定和T细胞功能的贡献。

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.