TY - JOUR
T1 - The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice
AU - Morgan, Marc A.J.
AU - Muller, Pari S.S.
AU - Mould, Arne
AU - Newland, Stephen A.
AU - Nichols, Jennifer
AU - Robertson, Elizabeth J.
AU - Cooke, Anne
AU - Bikoff, Elizabeth K.
PY - 2013/2/13
Y1 - 2013/2/13
N2 - The spontaneous destruction of insulin producing pancreatic beta cells in non-obese diabetic (NOD) mice provides a valuable model of type 1 diabetes. As in humans, disease susceptibility is controlled by the classical MHC class II genes that guide CD4+ T cell responses to self and foreign antigens. It has long been suspected that the dedicated class II chaperone designated HLA-DM in humans or H-2M in mice also makes an important contribution, but due to tight linkage within the MHC, a possible role played by DM peptide editing has not been previously tested by conventional genetic approaches. Here we exploited newly established germ-line competent NOD ES cells to engineer a loss of function allele. DM deficient NOD mice display defective class II peptide occupancy and surface expression, and are completely protected against type 1 diabetes. Interestingly the mutation results in increased proportional representation of CD4+Foxp3+ regulatory T cells and the absence of pathogenic CD4+ T effectors. Overall, this striking phenotype establishes that DM-mediated peptide selection plays an essential role in the development of autoimmune diabetes in NOD mice.
AB - The spontaneous destruction of insulin producing pancreatic beta cells in non-obese diabetic (NOD) mice provides a valuable model of type 1 diabetes. As in humans, disease susceptibility is controlled by the classical MHC class II genes that guide CD4+ T cell responses to self and foreign antigens. It has long been suspected that the dedicated class II chaperone designated HLA-DM in humans or H-2M in mice also makes an important contribution, but due to tight linkage within the MHC, a possible role played by DM peptide editing has not been previously tested by conventional genetic approaches. Here we exploited newly established germ-line competent NOD ES cells to engineer a loss of function allele. DM deficient NOD mice display defective class II peptide occupancy and surface expression, and are completely protected against type 1 diabetes. Interestingly the mutation results in increased proportional representation of CD4+Foxp3+ regulatory T cells and the absence of pathogenic CD4+ T effectors. Overall, this striking phenotype establishes that DM-mediated peptide selection plays an essential role in the development of autoimmune diabetes in NOD mice.
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U2 - 10.1371/journal.pone.0056738
DO - 10.1371/journal.pone.0056738
M3 - Article
C2 - 23418596
AN - SCOPUS:84873917187
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 2
M1 - e56738
ER -