title: The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B-cell lymphopoiesis and implicates microRNA-34a in diabetes protection.
abstract: 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. B cells have been shown to play a critical role in the priming of autoantigen-specific CD4(+) T cells 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 B cells as compared with NOD mice. Molecular analysis revealed that miR-34a expression was significantly higher in B-cell progenitors and marginal zone B cells 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(+) T cells proliferated inefficiently when primed by NOD.B10 Idd9.3 B cells 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(+) T cells and to T1D protection in NOD.B10 Idd9.3 mice.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Berry
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Budgeon
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Waldner
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D056426:Genetic Loci / Q000276:immunology*; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D012097:Repressor Proteins
keywords: B lymphocytes; Foxp1; Idd locus 9.3; Type 1 diabetes; microRNA-34a