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

被引:25
作者
Chen, Ting-Ting [1 ]
Tsai, Ming-Hsun [1 ]
Kung, John T. [2 ]
Lin, Kuo-I [3 ]
Decker, Thomas [4 ]
Lee, Chien-Kuo [1 ]
机构
[1] Natl Taiwan Univ, Grad Inst Immunol, Coll Med, Taipei 100, Taiwan
[2] Acad Sinica, Inst Mol Biol, Taipei 115, Taiwan
[3] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan
[4] Univ Vienna, Max F Perutz Labs, A-1030 Vienna, Austria
关键词
TOLL-LIKE RECEPTORS; T-BET; CHROMATIN IMMUNOPRECIPITATION; LYMPHOCYTE DIFFERENTIATION; STREPTOCOCCUS-PNEUMONIAE; AUTOANTIBODY PRODUCTION; TRANSCRIPTION FACTOR; IMMUNE-RESPONSE; DOWN-REGULATION; INNATE;
D O I
10.1084/jem.20151620
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:3025 / 3039
页数:15
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