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...
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doaj-7eebef782171470eb7208f3e17de928d2020-11-25T02:28:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5673810.1371/journal.pone.0056738The nonconventional MHC class II molecule DM governs diabetes susceptibility in NOD mice.Marc A J MorganPari S S MullerArne MouldStephen A NewlandJennifer NicholsElizabeth J RobertsonAnne CookeElizabeth K BikoffThe 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.http://europepmc.org/articles/PMC3572069?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marc A J Morgan Pari S S Muller Arne Mould Stephen A Newland Jennifer Nichols Elizabeth J Robertson Anne Cooke Elizabeth K Bikoff |
spellingShingle |
Marc A J Morgan Pari S S Muller Arne Mould Stephen A Newland Jennifer Nichols Elizabeth J Robertson Anne Cooke Elizabeth K Bikoff The nonconventional MHC class II molecule DM governs diabetes susceptibility in NOD mice. PLoS ONE |
author_facet |
Marc A J Morgan Pari S S Muller Arne Mould Stephen A Newland Jennifer Nichols Elizabeth J Robertson Anne Cooke Elizabeth K Bikoff |
author_sort |
Marc A J Morgan |
title |
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_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_sort |
nonconventional mhc class ii molecule dm governs diabetes susceptibility in nod mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
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. |
url |
http://europepmc.org/articles/PMC3572069?pdf=render |
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