Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect.
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.
Brims
Daniel R
DR
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Qian
Jie
J
Jarchum
Irene
I
Mikesh
Leann
L
Palmieri
Edith
E
Ramagopal
Udupi A
UA
Malashkevich
Vladimir N
VN
Chaparro
Rodolfo J
RJ
Lund
Torben
T
Hattori
Masakazu
M
Shabanowitz
Jeffrey
J
Hunt
Donald F
DF
Nathenson
Stanley G
SG
Almo
Steven C
SC
Dilorenzo
Teresa P
TP
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
D006183:H-2 Antigens; D006657:Histones; D010455:Peptides