CLASS II ANTIGEN PRESENTATION VIA CHAPERONE MEDIATED AUTOPHAGY

描述（由申请方提供）：源自外源和自身抗原的肽在MHC II类分子的背景下呈递，以供CD 4 + T细胞识别。II类分子通过细胞的内体网络，从外源性抗原以及内源性细胞表面和内体蛋白获得肽。令人惊讶的是，来自细胞质抗原的表位也由II类分子呈递。本提案的总体目标是了解调节II类细胞质Ag呈递的机制，并确定调节对自身和肿瘤Ag的免疫的新方法。随着肿瘤和病毒对I类呈递的颠覆，开发胞质Ag呈递的新途径仍然很重要。靶向用于II类呈递的特异性细胞质Ag提供了促进免疫识别和克服这种免疫逃避的独特方法。目前的建议集中在一个选择性的途径，伴侣介导的自噬（CMA），促进II类细胞质抗原呈递。我们建议，细胞质抗原选择性靶向的胞质分子伴侣蛋白在CMA过程中的蛋白水解。然后，所得的肽可以与膜转运蛋白LAMP-2A伴侣化，以易位到用于II类呈递的内体网络中。研究提出了定义的重要性伴侣，HSC 70和HSP 90在引导细胞质抗原的加工和易位到细胞器的II类呈递。LAMP-2基因的多种同种型在B细胞和黑素瘤中表达，可能通过自噬调节II类细胞质抗原呈递。提出研究以阐明单个LAMP- 2亚型在II类呈递途径中的作用。这个项目将提供关键的见解CMA的分子事件和必要的辅助因子，促进II类细胞质抗原的免疫识别。值得注意的是，自噬途径通常在肿瘤细胞中上调以促进肿瘤生长和存活。细胞自噬途径的这种变化可能会增强肿瘤抗原识别。本项目的研究将探讨不同的自噬途径在黑色素瘤细胞质抗原呈递中的重要性。这项工作也与我们对自身抗原的自身免疫和耐受诱导的理解有关。利用CMA途径的选择性也可能为疫苗开发的新方法提供机会。 公共卫生相关性：这项工作与我们对免疫系统如何区分自身和外来分子的一般理解有关。该项目对癌症有影响，因为自噬通常在肿瘤中上调，这可以用来促进肿瘤细胞的免疫识别。这些研究对理解自身免疫性也很重要，并为疫苗开发带来新的方法。

DESCRIPTION (provided by applicant): Peptides derived from foreign and self antigens are presented in the context of MHC class II molecules for recognition by CD4+ T cells. Class II molecules transit the endosomal network of cells, acquiring peptides from exogenous antigens as well as endogenous cell surface and endosomal proteins. Surprisingly, epitopes from cytoplasmic antigens also are presented by class II molecules. The overall goal of this proposal is to understand the mechanisms regulating class II cytoplasmic Ag presentation, and to identify new means to modulate immunity to self and tumor Ags. With subversion of class I presentation by tumors and viruses, exploiting novel pathways for cytoplasmic Ag presentation remains important. Targeting specific cytoplasmic Ags for class II presentation offers a unique approach to promote immune recognition and overcome such immune evasion. The current proposal focuses on a selective pathway, chaperone mediated autophagy (CMA) which facilitates class II cytoplasmic antigen presentation. We propose that cytoplasmic antigens are selectively targeted by cytosolic chaperones for proteolysis during CMA. The resulting peptides may then be chaperoned to a membrane transporter, LAMP-2A for translocation into the endosomal network for class II presentation. Studies are proposed to define the importance of chaperones, HSC70 and HSP90 in guiding cytoplasmic antigens for processing and translocation into organelles for class II presentation. Multiple isoforms of the LAMP-2 gene are expressed in B cells and melanomas, potentially regulating class II cytoplasmic antigen presentation by autophagy. Studies are proposed to elucidate the role of individual LAMP- 2 isoforms in class II presentation pathways. This project will offer critical insights into the molecular events and essential co-factors for CMA which faciliate class II access to cytoplasmic antigens for immune recognition. Notably, autophagy pathways are often up-regulated in tumor cells to promote tumor growth and survivial. Such changes in cellular autophagy pathways may enhance tumor antigen recognition. Studies in this project will examine the importance of distinct autophagy pathways in cytoplasmic antigen presentation by melanomas. This work also has relevance to our understanding of autoimmunity to self antigens and tolerance induction. Exploiting the selectivity of the CMA pathway may also offer opportunities for novel approaches to vaccine development. PUBLIC HEALTH RELEVANCE: This work has relevance to our general understanding of how the immune system distinguishes self and foreign molecules. The project has implications for cancer as autophagy is often up-regulated in tumors, and this could be exploited to promote immune recognition of tumor cells. These studies may also be important in understanding autoimmunty, and lead to new approaches for vaccine development.