STAT1 regulates marginal zone B cell differentiation in response to inflammation and infection with blood-borne bacteria

Author:

Chen Ting-Ting1ORCID,Tsai Ming-Hsun1,Kung John T.2ORCID,Lin Kuo-I3,Decker Thomas4ORCID,Lee Chien-Kuo1ORCID

Affiliation:

1. Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan

2. Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan

3. Genomics Research Center, Academia Sinica, Taipei 115, Taiwan

4. Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria

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.

Funder

Ministry of Science and Technology, Taiwan

National Health Research Institutes, Taiwan

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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