Antigen processing in the secretory pathway

Nilabh，2 R01 Al 060040-06A1 NiJabh，ROl Al 060040-06A 1 摘要 我们研究的长期目标是理解和操纵免疫监视。抗原处理机制可以进行数千次监视。抗原加工在细胞表面产生数千种肽/MHC II类复合物（pMHC I）作为潜在的配体细胞配体COB与教科书中的CD 8 T细胞模型相反。与教科书中经常描述的最终抗原肽在细胞质中产生的模型相反，最近的研究结果表明，细胞质中的抗原加工在内质网（ER）中继续进行。蛋白酶继续在内质网（ER）。蛋白酶介导ER中抗原前体的修剪的抗原修剪被称为ERAAP，其与抗原加工相关。在ERAAP缺陷者中，ER氨肽酶与抗原加工相关。ERAAP缺陷小鼠。ER修剪的缺乏破坏了正常的自身pMHC II库。在Manv小鼠中，修剪破坏了正常的自身pMHC库。Mani pMHC I缺失，并且伴随着大量新的pMHC I出现在ERAAP缺陷细胞的表面上。独特的pMHC I细胞的损失和获得。在野生型小鼠对ERAAP小鼠和ERAAP缺陷型小鼠中，这种丧失导致了强烈的相互免疫应答。 E 玉米 - 铜 在这里，我们提出填补我们理解的空白：（a）在ERAAP不存在或不存在的情况下产生的独特免疫原性pMHC I的结构和起源，（B）通过质谱法对在ERAAP存在或不存在的情况下产生的pMHC I库进行全面分析，和（c）质谱法的细胞机制，（c）用于在ERAAP缺陷型抗原细胞中引发对ERAAP缺陷型COB pMHC中的独特pMHC I的CD 8 T细胞应答。我们预期这些结果将提供对抗原的更深入的理解。我们预期这些结果将提供对加工途径以及如何操纵该途径以调节免疫原性的更深入的理解。 Moo '.. （0D 库姆。 CEP 凸轮 COO -0'0

Nilabh, 2 R01 Al 060040-06A1 NiJabh, ROl AI 060040-06A 1 ABSTRACT The long term goal of our research is to understand and manipulate research is to understand and manipulate immune surveillance. The antigen processing mechanisms yie,lds thousands of surveillance. The antigen processing yields thousands of peptide/MHC class II complexes (pMHC I) on the cell surface as potential ligands cell ligand COB Contrary to text book models for CD8 T cells. Contrary to text book models which often depict the final final antigenic peptide being generated in the cytoplasm, recent findings show that cytoplasm, findings that antigen processing continues in the endoplasmic reticulum (ER). The protease continues in the endoplasmic reticulum (ER). protease the trimming of antigenic that mediates the trimming of antigenic precursors in the ER is called ERAAP, fa ft associated with antigen processing. In ERAAP-deficien the ER aminopeptidase associated with antigen processing. In ERAAP-deficien mice. absence of ER trimming disrupts the normal self-pMHC IIrepertoire. Manv mice, trimming disrupts the normal self-pMHC repertoire. Mani pMHC I are missing and concomitantly a large set of novel pMHC I emerges on on the surface of ERAAP-deficient cells. The loss and gain of unique pMHC I cells. The loss and results in Vigorous reciprocal immune responses in wild-type versus ERAAP vigorous versus ERAAPdeficient mice. E Corn -cu Here we propose to fill the gaps in our understanding of (a) the structure we and origin of the unique immunogenic pMHC I generated in the absence of absence ERAAP, (b) global analysis of the pMHC I repertoire generated in the presence the presence or absence of ERAAP by mass-spectrometry, and (c) the cellular mechanisms mass-spectrometry, (c) the used for eliciting CD8 T cell responses to unique pMHC I in ERAAP deficient COB pMHC in ERAAP deficient antiger cells. We anticipate the results to provide a deeper understanding of the antiger We anticipate the results to provide a deeper understanding processing pathway and how the pathway can be manipulated to regulate can manipulated to regulate immunogenicity. moo '.. (0D Qom. cep cam coo -0'0