title: The nonconventional MHC class II molecule DM governs diabetes susceptibility in NOD mice.
abstract: 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.
authors: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors: Marc A J
authors: MA
authors: Morgan
authors: Pari S S
authors: PS
authors: Muller
authors: Arne
authors: A
authors: Mould
authors: Stephen A
authors: SA
authors: Newland
authors: Jennifer
authors: J
authors: Nichols
authors: Elizabeth J
authors: EJ
authors: Robertson
authors: Anne
authors: A
authors: Cooke
authors: Elizabeth K
authors: EK
authors: Bikoff
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C489628:H-2M antigen, mouse; D000949:Histocompatibility Antigens Class II; C045084:invariant chain