Redirection of B cell responsiveness by transforming growth factor β receptor

Abstract

The multifunctional transforming growth factor β receptor (TβR) 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 TβR 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 TβR-dependent transcriptome changes by comparative gene expression profiling of normal and TβR-deficient primary B cells. The data reveal TβR-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 TβR, 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 C-γ2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2+ release, and cell survival are enhanced in transforming growth factor-β-sensitive B cells. The data provide a molecular basis for TβR-mediated inhibition of B cell responsiveness and indicate that TβR maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to microenvironmental cues.