Redirection of B cell responsiveness by transforming growth factor β receptor

被引:44
|
作者
Roes, J [1 ]
Choi, BK [1 ]
Cazac, BB [1 ]
机构
[1] UCL, Windeyer Inst Med Sci, Dept Immunol & Mol Pathol, London W1T 4JF, England
关键词
D O I
10.1073/pnas.0731875100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The multifunctional transforming growth factor 13 receptor (TOR) ligand pair plays a central role in the regulation of lymphocyte homeostasis and prevention of autoimmunity. Although the mechanisms underlying the induction of transcriptional modulators by TbetaR have been studied in considerable detail, relatively little is known about the regulatory pathways targeted. To shed light on the mechanisms involved in negative regulation of B cell responses we identified TbetaR-dependent transcriptome changes by comparative gene expression profiling of normal and TbetaR-deficient primary B cells. The data reveal TbetaR-mediated induction of inhibitors of antigen receptor signaling (Ship-1, CD72) as well as inhibitors of the Jak/Stat pathway and signaling by means of Toll-like receptors (SOCS1,3). These inhibitory effects are complemented by induction of anti proliferative transcription factors. In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca(2+) flux (inositol trisphosphate receptor subtype 2) are induced by TbetaR, indicating enhancement of the Ca(2+) storage/release system and chemotactic responses. Suppression of proapoptotic genes suggests support of cell survival. Confirming the shift in B cell responsiveness, antigen-receptor-mediated activation of Syk and phospholipase C-gamma2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca(2+) release, and cell survival are enhanced in transforming growth factor-beta-sensitive B cells. The data provide a molecular basis for TbetaR-mediated inhibition of B cell responsiveness and indicate that TbetaR maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to micro-environmental cues.
引用
收藏
页码:7241 / 7246
页数:6
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