The long-term goal of this application is to understand the antigen processing mechanism by which endogenously synthesized proteins yield precisely cleaved peptide/MHC class I complexes on the cell surface. The expression of these peptide/MHC I complexes is essential for 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 peptide/MHC complexes is an important mechanism by which tumor cells and pathogens escape immune surveillance. We have developed novel cellular, biochemical and genetic techniques for analysis of naturally processed antigenic peptides. These techniques allow the direct analysis of the final processed peptides products, and for the first time, their proteolytic intermediates that are generated in the cytosol and in the ER. Here we propose to test different hypotheses on, (a) how the antigen processing steps in the cytosol and in the ER shape this pool of naturally processed peptides available for presentation by MHC class I molecules, and (b) how peptide trimming in the ER results in the generation and display of precisely cleaved peptides by the MHC I molecules on the cell surface. We anticipate that the answer to these questions will improve our understanding of the key factors that determine epitope selection, epitope dominance and the efficiency of the antigen processing pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039548-08
Application #
6688336
Study Section
Immunobiology Study Section (IMB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
1997-01-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
8
Fiscal Year
2004
Total Cost
$297,794
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Prasad, Sharanya; Starck, Shelley R; Shastri, Nilabh (2016) Presentation of Cryptic Peptides by MHC Class I Is Enhanced by Inflammatory Stimuli. J Immunol 197:2981-2991
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; Kanaseki, Takayuki; Escobar, Hernando et al. (2010) Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells. J Immunol 184:3033-42
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 (2010) Cross-presentation of peptides from intracellular pathogens by MHC class I molecules. Ann N Y Acad Sci 1183:237-50
Blanchard, Nicolas; Shastri, Nilabh (2008) Coping with loss of perfection in the MHC class I peptide repertoire. Curr Opin Immunol 20:82-8

Showing the most recent 10 out of 11 publications