title: Interferon-alpha triggers B cell effector 1 (Be1) commitment.
abstract: B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-γ play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-α triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-γ gene imprinting factors. IFN-α primed naive B-cells for IFN-γ production and increased IFN-γ gene responsiveness to IL-12. IFN-γ continues this polarization by re-inducing T-bet and up-regulating IL-12Rβ2 expression. IFN-α and IFN-γ therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-α, IFN-γ and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.
authors.affiliation: INSERM U-1012 and Université Paris-Sud, Bicêtre, France.
authors.forename: Marie-Ghislaine
authors.initials: MG
authors.lastname: de Goër de Herve
authors.forename: Deniz
authors.initials: D
authors.lastname: Durali
authors.forename: Bamory
authors.initials: B
authors.lastname: Dembele
authors.forename: Massimo
authors.initials: M
authors.lastname: Giuliani
authors.forename: Tu-Anh
authors.initials: TA
authors.lastname: Tran
authors.forename: Bruno
authors.initials: B
authors.lastname: Azzarone
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: Yassine
authors.initials: Y
authors.lastname: Taoufik
mesh_terms: D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D010641:Phenotype; D050797:STAT4 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D016898:Interferon-alpha; D050797:STAT4 Transcription Factor