title: Immune surveillance for ERAAP dysfunction.
abstract: The ER aminopeptidase associated with antigen processing, ERAAP (or ERAP1), is essential for trimming peptides that are presented by MHC class I molecules. ERAP1 is inhibited by human cytomegalovirus, and ERAP1 polymorphisms are associated with autoimmune diseases. How the immune system detects ERAAP dysfunction, however, is unknown. We have shown previously that ERAAP-deficient cells present an immunogenic pMHC I repertoire, that elicits CD8+ T cell response in WT mice. Additionally, we discovered that the WT CD8+ T cells recognized novel peptides presented by non-classical, or MHC class Ib, molecules on ERAAP-deficient cells. The MHC Ib restricted WT CD8 T cells eliminated ERAAP-deficient cells in vitro and in vivo. We identified the FL9 peptide, presented by Qa-1(b), a MHC class Ib molecule exclusively on ERAAP-deficient cells. Remarkably, T cells specific for the FL9-Qa-1(b) complex were frequent in naïve WT mice, and had an antigen-experienced phenotype. Thus, novel non-classical pQa-1(b) complexes direct cytotoxic T cells to target cells with defective peptide processing in the endoplasmic reticulum. Here, we discuss the implications of our findings, and the possible roles of pMHC Ib-specific T cells in immune surveillance for ERAAP dysfunction.
authors: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
authors: Niranjana A
authors: NA
authors: Nagarajan
authors: Nilabh
authors: N
authors: Shastri
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D007931:Leucyl Aminopeptidase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D015778:Minor Histocompatibility Antigens
chemical_list: D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human; D007931:Leucyl Aminopeptidase; C456799:puromycin-insensitive leucyl-specific aminopeptidase