The long-term goal of our research is to understand and manipulate the antigen processing mechanisms that yields thousands of peptide/MHC class I complexes on the cell surface. Contrary to the text book model which depicts the antigenic peptides being generated solely in the cytoplasm, recent findings indicate that antigen processing occurs both in the cytoplasm and continues in the secretory pathway specifically the endoplasmic reticulum (ER). The protease that mediates the trimming of antigenic peptides has recently been identified and termed ERAAP, for an ER aminopeptidase associated with antigen processing. Here we propose to fill the gaps in our understanding of how peptide trimming occurs in the ER and its impact on the CD8 T cell repertoire in a physiological context. We will use the unique tools we have developed in our laboratory for this analysis. These include (a) the ERAAP knock-out mice, and (b) novel methods for analysis of final output of the antigen processing pathway as well as the elusive proteolytic intermediates that are generated in normal and professional antigen presenting cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060040-04
Application #
7173914
Study Section
Immunobiology Study Section (IMB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2004-02-15
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$324,278
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
Guan, Jian; Yang, Soo Jung; Gonzalez, Federico et al. (2017) Antigen Processing in the Endoplasmic Reticulum Is Monitored by Semi-Invariant ?? TCRs Specific for a Conserved Peptide-Qa-1b MHC Class Ib Ligand. J Immunol 198:2017-2027
Nagarajan, Niranjana A; de Verteuil, Danielle A; Sriranganadane, Dev et al. (2016) ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules. J Immunol 197:1035-43
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
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