title: ERAP1 functions override the intrinsic selection of specific antigens as immunodominant peptides, thereby altering the potency of antigen-specific cytolytic and effector memory T-cell responses.
abstract: Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a critical component of the adaptive immune system that has been shown to increase or decrease the presentation of specific peptides on MHC class I molecules. Here, we have demonstrated that ERAP1 functions are not only important during the presentation of antigen-derived peptides, but these functions can also completely change which antigen-derived peptides ultimately become selected as immunodominant T-cell epitopes. Our results suggest that ERAP1 may do this by destroying epitopes that would otherwise become immunodominant in the absence of adequate ERAP1 functionality. We further establish that ERAP1-mediated influences on T-cell functions are both qualitative and quantitative, by demonstrating that loss of ERAP1 function redirects CTL killing toward a different set of antigen-derived epitopes and increases the percent of antigen-specific memory T cells elicited by antigen exposure. As a result, our studies suggest that normal ERAP1 activity can act to suppress the numbers of T effector memory cells that respond to a given antigen. This unique finding may shed light on why certain ERAP1 single nucleotide polymorphisms are associated with several autoimmune diseases, for example, by significantly altering the robustness and quality of CD8+ T-cell memory responses to antigen-derived peptides.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: David P W
authors.initials: DP
authors.lastname: Rastall
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA Department of Pediatrics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA amalfit1@msu.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D056704:Adaptive Immunity; D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060966:Clonal Selection, Antigen-Mediated; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D010455:Peptides / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D016207:Cytokines; D016056:Immunodominant Epitopes; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D000626:Aminopeptidases; C509944:ERAP1 protein, mouse
keywords: adaptive immune responses; antigen presentation; endoplasmic reticulum aminopeptidase-1; memory T-cells
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