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J Exp Med. 2016 May 2;213(5):733-50. doi: 10.1084/jem.20151724. Epub 2016 Apr 11.

B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6.

Author information

1
Seattle Children's Research Institute, Seattle, WA 98105 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195.
2
Seattle Children's Research Institute, Seattle, WA 98105.
3
Benaroya Research Institute, Seattle, WA 98101.
4
Seattle Children's Research Institute, Seattle, WA 98105 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195.
5
Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
6
Seattle Children's Research Institute, Seattle, WA 98105 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195 drawling@uw.edu.

Abstract

Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed. In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development. In contrast, B cells functioning as antigen-presenting cells initiate CD4(+) T cell activation and IFN-γ production, and strikingly, B cell-intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity. Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development. Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein. Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.

PMID:
27069113
PMCID:
PMC4854732
DOI:
10.1084/jem.20151724
[Indexed for MEDLINE]
Free PMC Article

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