Antigen processing in the secretory pathway

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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