Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect
Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect
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DOI：
10.1093/intimm/dxp127
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
DiLorenzo, Teresa P.
中科院分区：
文献类型：
--
作者：
Brims, Daniel R.;Qian, Jie;DiLorenzo, Teresa P.
1型糖尿病（T1D）是一种自身免疫性疾病，其特征是T细胞介导的胰岛素生成胰腺β细胞的破坏。在人类和非肥胖糖尿病（NOD）小鼠T1D模型中，II类MHC等位基因是疾病易感性的主要决定因素。然而，I类MHC基因也会影响风险。这些发现与T1D发病过程中CD4（+）和CD8(+) T细胞的需求一致。尽管大量的工作已经允许识别多种机制来解释特定的II类MHC等位基因对糖尿病的保护作用，但检查I类等位基因的保护作用的研究还缺乏。在这里，我们通过对小鼠I类MHC分子H-2K（wm7）进行生化和结构分析来探讨这个问题，该分子在NOD小鼠中具有糖尿病保护作用。我们发现，H-2K（wm7）分子主要由单一的自肽VNDIFERI占据，来源于普遍存在的蛋白质组蛋白H2B。这一意想不到的发现表明，H-2K（wm7）无法支持T1D的发展可能是由于，至少在一定程度上，来自关键β细胞抗原的肽未能充分竞争结合并提交给T细胞。单一肽的主要表现也可能影响t细胞的选择，可能导致选择致糖尿病性CD8(+) t细胞库的能力降低。据报道，与t1d保护HLA-A*31结合的主要肽之一是组蛋白衍生的，这表明我们的发现可能转化为人类糖尿病保护I类MHC分子。
Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD4(+) and CD8(+) T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2K(wm7), which exerts a diabetes-protective effect in NOD mice. We have found that H-2K(wm7) molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2K(wm7) to support T1D development could be due, at least in part, to the failure of peptides from critical beta-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD8(+) T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.