Antigen processing in the secretory pathway

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DESCRIPTION (provided by applicant): The long term goal of our research is to understand and manipulate immune surveillance pathways. The antigen processing mechanisms yields thousands of peptide/MHC class I complexes (pMHC I) on the cell surface as potential ligands for CD8 T cells. Contrary to text book models which often depict the final antigenic peptide being generated in the cytoplasm itself, recent findings have shown that antigen processing continues in the endoplasmic reticulum (ER). The protease that trims antigenic precursors in the ER is called ERAAP (or ERAP1), for the ER aminopeptidase associated with antigen processing. In ERAAP-deficient mice, lack of peptide trimming in the ER disrupts the normal peptide repertoire presented by the classical (MHC Ia) and surprisingly, non-classical (MHC Ib) as well: many pMHC I go missing and concomitantly many novel, highly immunogenic 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. Here we propose to test the hypothesis that the novel peptides presented in ERAAP-deficient cells are structurally distinct because they represent unedited versions of normally trimmed peptides or those that were destroyed by ERAAP. We will determine the structure and origin of the unique immunogenic peptides by mass spectrometry and T-cell based assays. In addition, because polymorphisms in ERAP1 have been associated with autoimmune diseases (ankylosing spondylitis and psoriasis) we will test the hypothesis that the composition of the peptide repertoire is influenced not only by polymorphic MHC molecules themselves, but also by polymorphisms in ERAAP. We anticipate the results of this proposal to provide a deeper understanding of the antigen processing pathway and how the pathway can be manipulated to regulate immunogenicity.