Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013;8(2):e56738. doi: 10.1371/journal.pone.0056738. Epub 2013 Feb 13.
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.
非肥胖型糖尿病（NOD）小鼠中胰岛素产生的胰岛β细胞的自发性破坏为 1 型糖尿病提供了有价值的模型。与人类一样，疾病易感性受经典 MHC II 类基因控制，这些基因指导 CD4(+)T 细胞对自身和外来抗原的反应。长期以来，人们一直怀疑人类中专门的 II 类伴侣分子 HLA-DM 或小鼠中的 H-2M 也做出了重要贡献，但由于 MHC 内的紧密连锁，DM 肽编辑可能发挥的作用以前尚未通过传统的遗传方法进行测试。在这里，我们利用新建立的具有种系能力的 NOD ES 细胞来设计功能丧失等位基因。DM 缺陷型 NOD 小鼠表现出 II 类肽占据和表面表达缺陷，并完全免受 1 型糖尿病的影响。有趣的是，该突变导致 CD4(+)Foxp3(+)调节性 T 细胞的比例增加，而致病性 CD4(+)T 效应物则缺失。总的来说，这种显著的表型表明，DM 介导的肽选择在 NOD 小鼠自身免疫性糖尿病的发展中起着至关重要的作用。
