期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 44, 期 6, 页码 1716-1727出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.201344116
关键词
B lymphocytes; Foxp1; Idd locus 9; 3; microRNA-34a; Type 1 diabetes
类别
资金
- Pennsylvania State College of Medicine
- Ono Pharmaceutical Co., Ltd.
NOD.B10 Idd9.3 mice are congenic for the insulin-dependent diabetes (Idd) Idd9.3 locus, which confers significant type 1 diabetes (T1D) protection and encodes 19 genes, including microRNA (miR)-34a, from T1D-resistant C57BL/10 mice. Bcells have been shown to play a critical role in the priming of autoantigen-specific CD4+ Tcells in T1D pathogenesis in non-obese diabetic (NOD) mice. We show that early B-cell development is impaired in NOD.B10 Idd9.3 mice, resulting in the profound reduction of transitional and mature splenic Bcells as compared with NOD mice. Molecular analysis revealed that miR-34a expression was significantly higher in B-cell progenitors and marginal zone Bcells from NOD.B10 Idd9.3 mice than in NOD mice. Furthermore, miR-34a expression in these cell populations inversely correlated with levels of Foxp1, an essential regulator of B-cell lymphopoiesis, which is directly repressed by miR-34a. In addition, we show that islet-specific CD4+ Tcells proliferated inefficiently when primed by NOD.B10 Idd9.3 Bcells in vitro or in response to endogenous autoantigen in NOD.B10 Idd9.3 mice. Thus, Idd9.3-encoded miR-34a is a likely candidate in negatively regulating B-cell lymphopoiesis, which may contribute to inefficient expansion of islet-specific CD4+ Tcells and to T1D protection in NOD.B10 Idd9.3 mice.
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