title: A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla.
abstract: Medullary thymic epithelial cells (mTECs) are critical in establishing and maintaining the appropriate microenvironment for negative selection and maturation of immunocompetent T cells with a self-tolerant T cell antigen receptor repertoire. Cues that direct proliferation and maturation of mTECs are provided by members of the tumor necrosis factor (TNF) superfamily expressed on developing thymocytes. Here we demonstrate a negative role of the morphogen TGF-β in tempering these signals under physiological conditions, limiting both growth and function of the thymic medulla. Eliminating TGF-β signaling specifically in TECs or by pharmacological means increased the size of the mTEC compartment, enhanced negative selection and functional maturation of medullary thymocytes as well as the production of regulatory T cells, thus reducing the autoreactive potential of peripheral T cells.
authors.affiliation: Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hauri-Hohl
authors.affiliation: 1] Laboratory of Pediatric Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. [2] Basel University's Hospital, Basel, Switzerland.
authors.forename: Saulius
authors.initials: S
authors.lastname: Zuklys
authors.affiliation: 1] Laboratory of Pediatric Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. [2] Basel University's Hospital, Basel, Switzerland. [3] Developmental Immunology, Department of Pediatrics, University of Oxford, Oxford, UK. [4] These authors contributed equally to this work.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Holländer
authors.affiliation: 1] Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA. [2] These authors contributed equally to this work.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C499308:Rag2 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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