Aryl hydrocarbon receptor is required for optimal B‐cell proliferation

• Published in: The EMBO journal Vol. 36; no. 1; pp. 116 - 128
• Main Authors: Villa, Matteo, Gialitakis, Manolis, Tolaini, Mauro, Ahlfors, Helena, Henderson, Colin J, Wolf, C Roland, Brink, Robert, Stockinger, Brigitta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.01.2017; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: aryl hydrocarbon receptor; B cells; B-Lymphocytes - physiology; Cell Proliferation; Cellular biology; cyclin O; Cyclins - metabolism; Cytochrome P-450 CYP1A1 - biosynthesis; EMBO19; Gene Expression Profiling; Hydrocarbons; Interleukin-4 - metabolism; proliferation; Receptors, Antigen, B-Cell - metabolism; Receptors, Aryl Hydrocarbon - deficiency; Receptors, Aryl Hydrocarbon - metabolism; Transcription factors; Transcription, Genetic; Translocation; cyclin O; B cells; proliferation; aryl hydrocarbon receptor
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201695027

The aryl hydrocarbon receptor (AhR), a transcription factor known for mediating xenobiotic toxicity, is expressed in B cells, which are known targets for environmental pollutants. However, it is unclear what the physiological functions of AhR in B cells are. We show here that expression of Ahr in B cells is up‐regulated upon B‐cell receptor (BCR) engagement and IL‐4 treatment. Addition of a natural ligand of AhR, FICZ, induces AhR translocation to the nucleus and transcription of the AhR target gene Cyp1a1 , showing that the AhR pathway is functional in B cells. AhR‐deficient ( Ahr −/− ) B cells proliferate less than AhR‐sufficient ( Ahr +/+ ) cells following in vitro BCR stimulation and in vivo adoptive transfer models confirmed that Ahr −/− B cells are outcompeted by Ahr +/+ cells. Transcriptome comparison of AhR‐deficient and AhR‐sufficient B cells identified cyclin O ( Ccno ), a direct target of AhR, as a top candidate affected by AhR deficiency. Synopsis The transcription factor AhR links environmental stimuli to the maintenance of optimal proliferation in B cells. B‐cell receptor stimulation increases AhR levels and sensitivity to ligands, which influence the ability to enter into the cell cycle. AhR is expressed at low level in all mature B cells, but strongly up‐regulated by B‐cell receptor‐mediated activation. Induction of AhR upon B‐cell receptor stimulation enhances the sensitivity of the AhR pathway to available ligands. AhR deficiency impairs B‐cell proliferation in vitro and in vivo and thereby negatively affects the generation of high‐affinity antibodies. Cyclin O ( Ccno ) was identified as one of the top AhR‐regulated genes, up‐regulated about 8 h after activation in AhR‐sufficient B cells, but not detectable in AhR‐deficient B cells. Graphical Abstract The transcription factor AhR links sensing of environmental stimuli to the regulation of B‐cell proliferation by promoting the ability of B cells to enter the cell cycle.