title: Compensatory mechanisms allow undersized anchor-deficient class I MHC ligands to mediate pathogenic autoreactive T cell responses.
abstract: Self-reactive T cells must escape thymic negative selection to mediate pathogenic autoimmunity. In the NOD mouse model of autoimmune diabetes, several β cell-cytotoxic CD8 T cell populations are known, with the most aggressive of these represented by AI4, a T cell clone with promiscuous Ag-recognition characteristics. We identified a long-elusive β cell-specific ligand for AI4 as an unusually short H-2D(b)-binding 7-mer peptide lacking a C-terminal anchor residue and derived from the insulin A chain (InsA14-20). Crystallography reveals that compensatory mechanisms permit peptides lacking a C-terminal anchor to bind sufficiently to the MHC to enable destructive T cell responses, yet allow cognate T cells to avoid negative selection. InsA14-20 shares two solvent-exposed residues with previously identified AI4 ligands, providing a structural explanation for AI4's promiscuity. Detection of AI4-like T cells, using mimotopes of InsA14-20 with improved H-2D(b)-binding characteristics, establishes the AI4-like T cell population as a consistent feature of the islet infiltrates of NOD mice. Our work establishes undersized peptides as previously unrecognized targets of autoreactive CD8 T cells and presents a strategy for their further exploration as Ags in autoimmune disease.
authors: The Jackson Laboratory, Bar Harbor, ME 04609;
authors: Deanna
authors: D
authors: Lamont
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors: Gayatri
authors: G
authors: Mukherjee
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;
authors: P Rajesh
authors: PR
authors: Kumar
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors: Dibyendu
authors: D
authors: Samanta
authors: The Jackson Laboratory, Bar Harbor, ME 04609;
authors: Caroline G
authors: CG
authors: McPhee
authors: St. Vincent's Institute, Fitzroy, Victoria 3065, Australia; Department of Medicine, The University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria 3065, Australia; and.
authors: Thomas W H
authors: TW
authors: Kay
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;
authors: Steven C
authors: SC
authors: Almo
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461 teresa.dilorenzo@einstein.yu.edu dave.serreze@jax.org.
authors: Teresa P
authors: TP
authors: DiLorenzo
authors: The Jackson Laboratory, Bar Harbor, ME 04609; teresa.dilorenzo@einstein.yu.edu dave.serreze@jax.org.
authors: David V
authors: DV
authors: Serreze
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D013329:Structure-Activity Relationship
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides