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The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572069/ https://www.ncbi.nlm.nih.gov/pubmed/23418596 http://dx.doi.org/10.1371/journal.pone.0056738 |
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author | Morgan, Marc A. J. Muller, Pari S. S. Mould, Arne Newland, Stephen A. Nichols, Jennifer Robertson, Elizabeth J. Cooke, Anne Bikoff, Elizabeth K. |
author_facet | Morgan, Marc A. J. Muller, Pari S. S. Mould, Arne Newland, Stephen A. Nichols, Jennifer Robertson, Elizabeth J. Cooke, Anne Bikoff, Elizabeth K. |
author_sort | Morgan, Marc A. J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3572069 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35720692013-02-15 The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice Morgan, Marc A. J. Muller, Pari S. S. Mould, Arne Newland, Stephen A. Nichols, Jennifer Robertson, Elizabeth J. Cooke, Anne Bikoff, Elizabeth K. PLoS One Research Article 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. Public Library of Science 2013-02-13 /pmc/articles/PMC3572069/ /pubmed/23418596 http://dx.doi.org/10.1371/journal.pone.0056738 Text en © 2013 Morgan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Morgan, Marc A. J. Muller, Pari S. S. Mould, Arne Newland, Stephen A. Nichols, Jennifer Robertson, Elizabeth J. Cooke, Anne Bikoff, Elizabeth K. The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice |
title | The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice |
title_full | The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice |
title_fullStr | The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice |
title_full_unstemmed | The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice |
title_short | The Nonconventional MHC Class II Molecule DM Governs Diabetes Susceptibility in NOD Mice |
title_sort | nonconventional mhc class ii molecule dm governs diabetes susceptibility in nod mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572069/ https://www.ncbi.nlm.nih.gov/pubmed/23418596 http://dx.doi.org/10.1371/journal.pone.0056738 |
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