Antigen processing in the secretory pathway

我们研究的长期目标是了解和操纵免疫监视途径。抗原处理机制在细胞表面产生数以千计的多肽/MHC复合体(pMHC I和pMHC II)，分别作为CD8+和CD4+T细胞的潜在配体。在之前的资金支持下，我们发现抗原肽不仅在细胞质中被修剪，而且在内质网中也被ERAAP修剪，ERAAP是与抗原处理相关的ER氨基肽酶。这一关键概念现在是目前教科书中对抗原处理途径的描述的一部分。在ERAAP缺陷小鼠中，内质网中缺乏肽的修剪被发现扰乱了经典MHC Ia以及非经典MHC Ib分子的正常肽谱：许多pMHC I缺失，许多新的pMHC I出现在ERAAP缺陷细胞的表面。在野生型和ERAAP缺陷小鼠中，独特的多肽的丢失和获得导致了强烈的互惠免疫反应。 我们还发现ERAAP和MHC I在物理和功能上相互作用，截短的ERAAP结构域是MHC I肽呈递的主要负调控因子。出乎意料的是，我们还发现ERAAP还可以通过MHC II类分子调节多肽的呈递，从而调节CD4T细胞的反应。ERAAP的这些特性可能解释了最近的全基因组关联研究，这些研究表明ERAP1(人类与小鼠ERAAP的同源)的多态变异与强直性脊柱炎和牛皮癣等自身免疫性疾病有关。在这里，我们将测试ERAAP在调节MHC I和MHC II分子提供的多肽库中的作用的分子机制和后果。我们还将测试ERAAP多态通过特定的MHC分子影响多肽递呈的假设，这些MHC分子可能导致正常耐受的自体多肽成为免疫原性，从而导致自身免疫。我们期待这一结果为抗原处理途径提供新的见解，以及如何操纵这些途径来调节免疫原性和目前无法治愈的自身免疫性疾病。

The long term goal of our research is to understand and manipulate immune surveillance pathways. The antigen processing mechanisms yields thousands of peptide/MHC complexes (pMHC I and pMHC II) on the cell surface as potential ligands for CD8+ and CD4+ T cells respectively. With prior funding support we showed that antigenic peptides are trimmed not only in the cytoplasm, but also in the endoplasmic reticulum by ERAAP, the ER aminopeptidase associated with antigen processing. This key concept is now part of current text book descriptions of antigen processing pathways. In ERAAP-deficient mice, lack of peptide trimming in the ER has been found to disrupt the normal peptide repertoire by both classic MHC Ia as well as non-classical MHC Ib molecules: many pMHC I are missing and numerous novel pMHC I emerge on the surface of ERAAP-deficient cells. The loss and gain of unique peptides results in vigorous reciprocal immune responses in wild-type versus ERAAP-deficient mice. We have also discovered that ERAAP and MHC I interact physically and functionally and truncated ERAAPdomains serve as dominant negative regulators of MHC I peptide presentation. Unexpectedly, we also discovered that ERAAP can also regulate peptide presentation by MHC class II molecules and hence CD4 T cell responses as well. These properties of ERAAP may explain the recent genome wide association studies that have shown that polymorphic variants of ERAP1 (human ortholog of mouse ERAAP) are associated with autoimmune diseases such as ankylosing spondylitis and psoriasis. Here we will test the molecular mechanisms and consequences of ERAAP's role in regulating the peptide repertoires presented by MHC I and MHC II molecules. We will also test the hypothesis that ERAAP polymorphisms influence the peptide presentation by particular MHC molecules that could cause normally tolerated self-peptides to become immunogenic and thus cause autoimmunity. We anticipate the results to provide new insights into the antigen processing pathways and how these pathways could be manipulated to regulate immunogenicity and presently incurable autoimmune disorders.