The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B-cell lymphopoiesis and implicates microRNA-34a in diabetes protection

Gregory J. Berry, Lynn R. Budgeon, Timothy K. Cooper, Neil D. Christensen, Hanspeter Waldner

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1716-1727
Number of pages12
JournalEuropean Journal of Immunology
Volume44
Issue number6
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Lymphopoiesis
MicroRNAs
Type 1 Diabetes Mellitus
B-Lymphocytes
Inbred NOD Mouse
Congenic Mice
B-Lymphoid Precursor Cells
Autoantigens
Inbred C57BL Mouse
Insulin
Population
Genes

Keywords

  • B lymphocytes
  • Foxp1
  • Idd locus 9.3
  • MicroRNA-34a
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B-cell lymphopoiesis and implicates microRNA-34a in diabetes protection. / Berry, Gregory J.; Budgeon, Lynn R.; Cooper, Timothy K.; Christensen, Neil D.; Waldner, Hanspeter.

In: European Journal of Immunology, Vol. 44, No. 6, 2014, p. 1716-1727.

Research output: Contribution to journalArticle

Berry, Gregory J. ; Budgeon, Lynn R. ; Cooper, Timothy K. ; Christensen, Neil D. ; Waldner, Hanspeter. / The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B-cell lymphopoiesis and implicates microRNA-34a in diabetes protection. In: European Journal of Immunology. 2014 ; Vol. 44, No. 6. pp. 1716-1727.
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