The long term goal of this proposal is to understand the antigen processing mechanism by which endogenously synthesized or exogenous proteins yield precisely cleaved peptide/MHC class I complexes (pMHC I) on the cell surface. The expression of pMHC I is essential for the development and maintenance of the CD8+ cytotoxic T-cell repertoire and for immune responses specific for tumors, intracellular pathogens, allogeneic tissue grafts and self-tissues in autoimmunity. Failure to express pMHC I complexes is an important mechanism by which tumor cells and viral pathogens escape immune surveillance. We have developed novel cellular, biochemical and genetic techniques as well as model systems for analysis of naturally processed antigenic peptides. These methods allow the direct analysis of the final processed peptide products, and for the first time, their previously unknown proteolytic intermediates that are associated with cytoplasmic chaperones. Here we propose to test different hypotheses on how the early antigen processing steps shape the pool of naturally processed peptides available for presentation by MHC class I molecules. Furthermore, we will determine how exogenous antigens intersect with the endogenous antigen processing pathway and result in the display of pMHC I on the cell surface. We anticipate the answers will fill gaps in our understanding of the key factors that determine epitope selection, immunodominance and cross-presentation in the MHC class I antigen processing pathway. We anticipate that this research will improve our understanding of the mechanisms by which the immune system detects infected cells and tumors as well as self-tissues in autoimmunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Gondre-Lewis, Timothy A
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University of California Berkeley
Schools of Arts and Sciences
United States
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Shastri, Nilabh; Nagarajan, Niranjana; Lind, Kristin C et al. (2014) Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. Curr Opin Immunol 26:123-7
Nagarajan, Niranjana A; Shastri, Nilabh (2013) Immune surveillance for ERAAP dysfunction. Mol Immunol 55:120-2
Kanaseki, Takayuki; Lind, Kristin Camfield; Escobar, Hernando et al. (2013) ERAAP and tapasin independently edit the amino and carboxyl termini of MHC class I peptides. J Immunol 191:1547-55
Nagarajan, Niranjana A; Gonzalez, Federico; Shastri, Nilabh (2012) Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. Nat Immunol 13:579-86
Cardinaud, Sylvain; Starck, Shelley R; Chandra, Piyanka et al. (2010) The synthesis of truncated polypeptides for immune surveillance and viral evasion. PLoS One 5:e8692
Blanchard, Nicolas; Shastri, Nilabh (2010) Topological journey of parasite-derived antigens for presentation by MHC class I molecules. Trends Immunol 31:414-21
Blanchard, Nicolas; Shastri, Nilabh (2008) Coping with loss of perfection in the MHC class I peptide repertoire. Curr Opin Immunol 20:82-8
Kanaseki, Takayuki; Blanchard, Nicolas; Hammer, Gianna Elena et al. (2006) ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity 25:795-806