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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.

Original publication

DOI

10.1371/journal.pone.0056738

Type

Journal article

Journal

PLoS One

Publication Date

2013

Volume

8

Keywords

Animals, Antigens, Differentiation, B-Lymphocyte, Blotting, Western, Diabetes Mellitus, Type 1, Embryonic Stem Cells, Female, Forkhead Transcription Factors, Genetic Predisposition to Disease, Histocompatibility Antigens Class II, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Microscopy, Confocal, T-Lymphocytes, Regulatory, Thymus Gland