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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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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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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
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; 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