title: Redirection of B cell responsiveness by transforming growth factor beta receptor.
abstract: The multifunctional transforming growth factor beta receptor (TbetaR) 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 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 TbetaR, 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-gamma2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2+ 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 microenvironmental cues.
authors.affiliation: Department of Immunology and Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, 46 Cleveland Street, London W1T 4JF, United Kingdom. j.roes@ucl.ac.uk
authors.forename: Jurgen
authors.initials: J
authors.lastname: Roes
authors.forename: B Ken
authors.initials: BK
authors.lastname: Choi
authors.forename: Balthazar B
authors.initials: BB
authors.lastname: Cazac
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D001483:Base Sequence; D002455:Cell Division; D002470:Cell Survival; D018925:Chemokines / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C408982:CPG-oligonucleotide; D018925:Chemokines; D009838:Oligodeoxyribonucleotides; D011947:Receptors, Antigen, B-Cell; D018121:Receptors, Cytokine; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019204:GTP-Binding Proteins