title: STAT1 regulates marginal zone B cell differentiation in response to inflammation and infection with blood-borne bacteria.
abstract: Marginal zone B (MZ B) cells can rapidly produce antibody in response to infection with blood-borne encapsulated pathogens. Although TLR-mediated activation of MZ B is known to trigger humoral immune response, the signal cascade directing this response remains undefined. Here, we demonstrate that STAT1 plays an essential role in TLR-mediated antibody response of MZ B cells. Further, the TLR-induced IgM response is impaired in a type I and type II IFN-independent manner. Although activation, proliferation, and apoptosis are not affected, both differentiation into plasma cells and IgM production are impaired in Stat1-/-MZ B cells. Interestingly, STAT1 directly regulates the expression of Prdm1 (encodes BLIMP-1) by binding to its promoter, and Prdm1 expression is reduced in Stat1-/-MZ B cells. Restoration of BLIMP-1 to cells rescues TLR-induced IgM response. Moreover, Stat1-/-mice are more susceptible to S. pneumoniae infection, which can be rescued by the serum of bacteria-primed WT mice. The increased susceptibility to S. pneumoniae infection in Stat1-/-mice is also intrinsic to STAT1 requirement in MZ B cells. Collectively, these results define a differential regulation of TLR-mediated activation and differentiation of MZ B cells by STAT1 and reveal a STAT1-dependent, but IFN-independent, antibody response during infection and inflammation.
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Ting-Ting
authors.identifier: 0000-0002-4511-5413
authors.initials: TT
authors.lastname: Chen
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Ming-Hsun
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: John T
authors.identifier: 0000-0001-9052-1392
authors.initials: JT
authors.lastname: Kung
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Kuo-I
authors.initials: KI
authors.lastname: Lin
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
authors.forename: Thomas
authors.identifier: 0000-0001-9683-0620
authors.initials: T
authors.lastname: Decker
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan leeck@ntu.edu.tw.
authors.forename: Chien-Kuo
authors.identifier: 0000-0001-8189-6045
authors.initials: CK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D017848:Blood-Borne Pathogens; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007372:Interferons / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: C513258:Prdm1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014157:Transcription Factors; D007372:Interferons; D000074462:Positive Regulatory Domain I-Binding Factor 1