TY - JOUR
T1 - Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect
AU - Brims, Daniel R.
AU - Qian, Jie
AU - Jarchum, Irene
AU - Mikesh, Leann
AU - Palmieri, Edith
AU - Ramagopal, Udupi A.
AU - Malashkevich, Vladimir N.
AU - Chaparro, Rodolfo J.
AU - Lund, Torben
AU - Hattori, Masakazu
AU - Shabanowitz, Jeffrey
AU - Hunt, Donald F.
AU - Nathenson, Stanley G.
AU - Almo, Steven C.
AU - DiLorenzo, Teresa P.
N1 - Funding Information:
National Institutes of Health (AI033993 to D.F.H., AI007289 to S.G.N. and S.C.A., DK064315 and DK052956 to T.P.D., P60DK020541 to Albert Einstein College of Medicine’s Diabetes Research and Training Center); Juvenile Diabetes Research Foundation (to T.P.D.); Irma T. Hirschl/Monique Weill-Caulier Trust (to T.P.D.); the flow cytometry facility at Albert Einstein College of Medicine is supported by National Institutes of Health Cancer Center (P30CA013330).
PY - 2010/1/21
Y1 - 2010/1/21
N2 - Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic β 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-2Kwm7, which exerts a diabetes-protective effect in NOD mice. We have found that H-2Kwm7 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-2Kwm7 to support T1D development could be due, at least in part, to the failure of peptides from critical β-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.
AB - Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic β 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-2Kwm7, which exerts a diabetes-protective effect in NOD mice. We have found that H-2Kwm7 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-2Kwm7 to support T1D development could be due, at least in part, to the failure of peptides from critical β-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.
KW - Autoimmunity
KW - Diabetes
KW - MHC
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U2 - 10.1093/intimm/dxp127
DO - 10.1093/intimm/dxp127
M3 - Article
C2 - 20093428
AN - SCOPUS:77949900942
SN - 0953-8178
VL - 22
SP - 191
EP - 203
JO - International Immunology
JF - International Immunology
IS - 3
M1 - dxp127
ER -