title: The aryl hydrocarbon receptor controls cell-fate decisions in B cells.
abstract: Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool. In this study, we show that an environmental sensor, the aryl hydrocarbon receptor (AhR) is highly induced upon B cell activation and serves a critical role in regulating activation-induced cell fate outcomes. We find that AhR negatively regulates class-switch recombination ex vivo by altering activation-induced cytidine deaminase expression. We further demonstrate that AhR suppresses class switching in vivo after influenza virus infection and immunization with model antigens. In addition, by regulating Blimp-1 expression via Bach2, AhR represses differentiation of B cells into plasmablasts ex vivo and antibody-secreting plasma cells in vivo. These experiments suggest that AhR serves as a molecular rheostat in B cells to brake the effector response, possibly to facilitate optimal recall responses. Thus, AhR might represent a novel molecular target for manipulation of B cell responses during vaccination.
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065.
authors.forename: Bharat
authors.initials: B
authors.lastname: Vaidyanathan
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Ashutosh
authors.identifier: 0000-0003-3379-5236
authors.initials: A
authors.lastname: Chaudhry
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: William T
authors.identifier: 0000-0002-5712-1896
authors.initials: WT
authors.lastname: Yewdell
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814.
authors.forename: Davide
authors.identifier: 0000-0002-5256-1972
authors.initials: D
authors.lastname: Angeletti
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Biochemistry, Cellular, and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Yen
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Wheatley
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Howard Hughes Medical Institute, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 chaudhuj@mskcc.org.|Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D003564:Cytidine Deaminase / Q000502:physiology; D005260:Female; D017578:Immunoglobulin Class Switching; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000072317:Polychlorinated Dibenzodioxins; C513258:Prdm1 protein, mouse; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase