Redirection of B cell responsiveness by transforming growth factor receptor

The multifunctional transforming growth factor receptor (T R) 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 T R 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 T R-dependent transcriptome changes by comparative gene expression profiling of normal and T R-deficient primary B cells. The data reveal T R-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 antiproliferative transcription factors. In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca2 flux (inositol trisphosphate receptor subtype 2) are induced by T R, indicating enhancement of the Ca2 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 C2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2 release, and cell survival are enhanced in transforming growth factor-sensitive B cells. The data provide a molecular basis for T R-mediated inhibition of B cell responsiveness and indicate that T R maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to microenvironmental cues.