title: Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T-cell activation and differentiation.
abstract: Bone morphogenetic proteins (BMPs) are involved in patterning and cellular fate in various organs including the thymus. However, the redundancy of BMPs and their receptors have made it difficult to analyse their physiological roles. Here, we investigated the role of BMP signalling in peripheral CD4(+)  T cells by analysing the effects of an inhibitor of BMP signalling, dorsomorphin. Dorsomorphin suppressed phosphorylation of SMAD1/5/8, suggesting that BMP signalling naturally occurs in T cells. At high doses, dorsomorphin suppressed proliferation of T cells in a dose-dependent manner, inducing G1 arrest. Also, dorsomorphin suppressed Th17 and induced Treg-cell differentiation, while preserving Th2 differentiation. Dorsomorphin efficiently suppressed IL-2 production even at low doses in mouse CD4(+)  T cells, suggesting that the BMP-Smad signalling physiologically regulates IL-2 transcription in these cells. In addition, recombinant BMP2 induced a dose-dependent multiphasic pattern of IL-2 production, while Noggin suppressed IL-2 production at higher doses in Jurkat cells. Notably, BMP signalling controlled the phosphorylation of RUNX1, revealing the molecular nature of its effect. Collectively, we describe multiple effects of dorsomorphin and Noggin on T-cell activation and differentiation, demonstrating a physiological role for BMP signalling in these processes.
authors.affiliation: Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Motonao
authors.initials: M
authors.lastname: Osaki
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D050676:Core Binding Factor Alpha 2 Subunit / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051785:Smad Proteins / Q000276:immunology; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D007376:Interleukin-2; D011720:Pyrazoles; D011743:Pyrimidines; D012313:RNA; D051785:Smad Proteins; D000099176:Noggin Protein; C493728:RUNX1 protein, human; C516138:dorsomorphin