title: Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect.
abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD4(+) and CD8(+) T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2K(wm7), which exerts a diabetes-protective effect in NOD mice. We have found that H-2K(wm7) molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2K(wm7) to support T1D development could be due, at least in part, to the failure of peptides from critical beta-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD8(+) T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Brims
authors.forename: Jie
authors.initials: J
authors.lastname: Qian
authors.forename: Irene
authors.initials: I
authors.lastname: Jarchum
authors.forename: Leann
authors.initials: L
authors.lastname: Mikesh
authors.forename: Edith
authors.initials: E
authors.lastname: Palmieri
authors.forename: Udupi A
authors.initials: UA
authors.lastname: Ramagopal
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Malashkevich
authors.forename: Rodolfo J
authors.initials: RJ
authors.lastname: Chaparro
authors.forename: Torben
authors.initials: T
authors.lastname: Lund
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hattori
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shabanowitz
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hunt
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Nathenson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Teresa P
authors.initials: TP
authors.lastname: Dilorenzo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002469:Cell Separation; D003461:Crystallography; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D020836:Protein Structure, Quaternary
chemical_list: D006183:H-2 Antigens; D006657:Histones; D010455:Peptides