CLASS II ANTIGEN PRESENTATION VIA CHAPERONE MEDIATED AUTOPHAGY

描述(由申请人提供)：来自异源和自身抗原的多肽在MHC II类分子的背景下提出，以供CD4T细胞识别。第二类分子通过细胞的内体网络，从外源抗原以及内源细胞表面和内体蛋白中获取多肽。令人惊讶的是，细胞质抗原的表位也是由II类分子提出的。这项建议的总体目标是了解调节第二类胞浆抗原提呈的机制，并寻找新的方法来调节对自身和肿瘤抗原的免疫。随着肿瘤和病毒对I类抗原提呈的颠覆，探索胞浆抗原提呈的新途径仍然很重要。以特定的胞浆AGS为II类递呈提供了一种独特的方法来促进免疫识别和克服这种免疫逃避。目前的建议侧重于一种选择性途径，即伴侣介导的自噬(CMA)，它有助于II类细胞质抗原的呈递。我们认为在CMA过程中，胞质抗原被胞浆伴侣选择性地作为蛋白质降解的靶点。然后，产生的多肽可以伴随到膜转运体LAMP-2A上，以转位到内体网络中，用于II类递送。有人建议进行研究，以确定伴侣蛋白、HSC70和HSP90在引导细胞质抗原加工和转移到细胞器中用于II类呈递中的重要性。LAMP-2基因的多种异构体在B细胞和黑色素瘤中表达，可能通过自噬调节II类细胞质抗原的呈递。有人建议进行研究，以阐明单个LAMP-2亚型在II类递呈途径中的作用。这个项目将对CMA的分子事件和基本辅助因素提供关键的见解，CMA有助于II类细胞获得细胞质抗原以进行免疫识别。值得注意的是，自噬途径通常在肿瘤细胞中上调，以促进肿瘤的生长和存活。细胞自噬途径的这种变化可能会增强对肿瘤抗原的识别。在这个项目中的研究将检验不同的自噬途径在黑色素瘤的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源分子的一般理解有关。该项目对癌症有意义，因为自噬在肿瘤中经常上调，这可能被利用来促进对肿瘤细胞的免疫识别。这些研究可能对理解自身免疫也很重要，并导致疫苗开发的新方法。

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.