Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection
| Autor: | Arnauld Sergé, Mark J. McCarron, Saïdi M. Soudja, Magali Irla, Julien C. Marie |
|---|---|
| Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Genentech, Inc. [San Francisco], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre for Cellular and Molecular Biology of Inflammation, King‘s College London, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Central tolerance T cell Cellular differentiation Science T cells General Physics and Astronomy Autoimmunity Bone Marrow Cells Biology CXCR3 Models Biological General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Negative selection 0302 clinical medicine Transforming Growth Factor beta medicine Animals lcsh:Science Mice Knockout Multidisciplinary Thymocytes RANK Ligand Cell Differentiation Epithelial Cells General Chemistry T lymphocyte Transforming growth factor beta Cell biology 030104 developmental biology medicine.anatomical_structure [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology biology.protein [SDV.IMM]Life Sciences [q-bio]/Immunology lcsh:Q Signal transduction 030215 immunology Transforming growth factor Signal Transduction |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) Nature Communications Nature Communications, 2019, 10, pp.5690. ⟨10.1038/s41467-019-13456-z⟩ Nature Communications, Nature Publishing Group, 2019, 10, ⟨10.1038/s41467-019-13456-z⟩ |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-13456-z⟩ |
| Popis: | In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-β) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-β in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms. TGFβ is critical for limiting autoreactive responses of peripheral T cells. Here, the authors show that TGFβ signaling in thymocytes mediates elimination of self-reactive T cells and promotes the expression of self-antigens by medullary thymic epithelial cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|