Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells
Christopher J.M. Piper,
Elizabeth C. Rosser,
Kristine Oleinika,
Kiran Nistala,
Thomas Krausgruber,
André F. Rendeiro,
Aggelos Banos,
Ignat Drozdov,
Matteo Villa,
Scott Thomson,
Georgina Xanthou,
Christoph Bock,
Brigitta Stockinger,
Claudia Mauri
Affiliations
Christopher J.M. Piper
Centre for Rheumatology, Division of Medicine, University College London, London, UK
Elizabeth C. Rosser
Centre for Rheumatology, Division of Medicine, University College London, London, UK; University College London Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK; Versus Arthritis Centre for Adolescent Rheumatology at University College London, University College London Hospitals and Great Ormond Street Hospital, London, UK
Kristine Oleinika
Centre for Rheumatology, Division of Medicine, University College London, London, UK
Kiran Nistala
Centre for Rheumatology, Division of Medicine, University College London, London, UK
Thomas Krausgruber
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
André F. Rendeiro
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Aggelos Banos
Laboratory of Inflammation and Autoimmunity, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Ignat Drozdov
Bering Limited, London, TW2 5EA, UK
Matteo Villa
The Francis Crick Institute, London, NW1 1AT, UK
Scott Thomson
Centre for Rheumatology, Division of Medicine, University College London, London, UK
Georgina Xanthou
Cellular Immunology Lab, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Christoph Bock
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany
Brigitta Stockinger
The Francis Crick Institute, London, NW1 1AT, UK
Claudia Mauri
Centre for Rheumatology, Division of Medicine, University College London, London, UK; Corresponding author
Summary: Regulatory B cells (Bregs) play a critical role in the control of autoimmunity and inflammation. IL-10 production is the hallmark for the identification of Bregs. However, the molecular determinants that regulate the transcription of IL-10 and control the Breg developmental program remain unknown. Here, we demonstrate that aryl hydrocarbon receptor (AhR) regulates the differentiation and function of IL-10-producing CD19+CD21hiCD24hiBregs and limits their differentiation into B cells that contribute to inflammation. Chromatin profiling and transcriptome analyses show that loss of AhR in B cells reduces expression of IL-10 by skewing the differentiation of CD19+CD21hiCD24hiB cells into a pro-inflammatory program, under Breg-inducing conditions. B cell AhR-deficient mice develop exacerbated arthritis, show significant reductions in IL-10-producing Bregs and regulatory T cells, and show an increase in T helper (Th) 1 and Th17 cells compared with B cell AhR-sufficient mice. Thus, we identify AhR as a relevant contributor to the transcriptional regulation of Breg differentiation. : The transcriptional control of interleukin-10 (IL-10) in regulatory B cells (Bregs) remains undefined. Piper et al. identify the aryl hydrocarbon receptor (AhR) as an important transcription factor involved in Breg differentiation and show a direct role of AhR in the regulation of IL-10 transcription.
