title: Cutting Edge: IL-4, IL-21, and IFN-γ Interact To Govern T-bet and CD11c Expression in TLR-Activated B Cells.
abstract: T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction. Finally, IL-21, but not IFN-γ, promotes CD11c expression independent of T-bet. Using influenza virus and Heligmosomoides polygyrus infections, we show that these interactions function in vivo to determine whether T-bet(+) and CD11c(+) B cells are formed. These findings suggest that T-bet(+) B cells seen in health and disease share the common initiating features of TLR-driven activation within this circumscribed cytokine milieu.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Martin S
authors.initials: MS
authors.lastname: Naradikian
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Arpita
authors.initials: A
authors.lastname: Myles
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Kenneth J
authors.identifier: 0000-0001-8869-9503
authors.initials: KJ
authors.lastname: Roberts
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Lucas
authors.initials: L
authors.lastname: Dawson
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Ramin Sedaghat
authors.identifier: 0000-0003-2613-4050
authors.initials: RS
authors.lastname: Herati
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Wistar Institute, Philadelphia, PA 19104; and.
authors.forename: Susanne L
authors.identifier: 0000-0003-3297-3774
authors.initials: SL
authors.lastname: Linderman
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Erietta
authors.initials: E
authors.lastname: Stelekati
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Christopher
authors.initials: C
authors.lastname: Hunter
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Wistar Institute, Philadelphia, PA 19104; and.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Hensley
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cancro@mail.med.upenn.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D039521:CD11c Antigen / Q000096:biosynthesis / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: D039521:CD11c Antigen; D007378:Interleukins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051193:Toll-Like Receptors; D015847:Interleukin-4; D007371:Interferon-gamma; D000098546:Interleukin-21