The long term goal of our research is to understand and manipulate immune surveillance pathways. The MHC class I antigen processing pathway generates a vast repertoire of peptides as pMHC I ligands for the CD8 T cells. These pMHC I ligands inform the CD8 T cells of intracellular changes in the protein milieu caused by a virus infection or tumorigenic transformation. Not surprisingly, key steps of this pathway, such as the peptide transporter TAP, is frequently blocked by viruses and mutated in tumors. The immune system has also evolved counter strategies using NK cells to detect and eliminate cells with drastic changes in the pMHC repertoire due to defects in the antigen processing pathway. The ERAAP (or ERAP1), the ER aminopeptidase associated with antigen processing, is essential for generating the pMHC I repertoire. Recent studies with human autoimmune disorders, cytomegalovirus infected, and tumor cells have revealed that ERAAP expression is also altered in these conditions. However, the mechanism by which the immune system detects ERAAP dysfunction is not known. Here, we will test the hypothesis that a novel subpopulation of CD8 T cells, termed Qfl, with innate-like functions detects and eliminates cells with ERAAP deficiency. The Qfl CD8 T cells are specific for Qa-1b, non- classical MHC Ib molecule presenting the invariant FL9 peptide exclusively in ERAAP-deficient cells. The Qfl CD8 T cells can be detected, characterized and isolated using the Qa1/FL9 tetramer reagent. In well defined mouse models we will characterize the TCRs, function and developmental pathway of the Qfl subset of CD8 T cells to establish a potentially new paradigm for immune surveillance for defects in the antigen processing and presentation pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI101751-02
Application #
8503599
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2012-07-03
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$180,363
Indirect Cost
$62,863
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
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