Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection

Mark J. McCarron, Magali Irla, Arnauld Sergé, Saidi M’Homa Soudja and Julien C. Marie ()
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Mark J. McCarron: Cancer Research Center of Lyon (CRCL) UMR INSERM1052
Magali Irla: Centre d’Immunologie de Marseille Luminy (CIML), INSERM U1104, CNRS UMR 7280, Aix-Marseille Université UM2, F-13288 cedex 09
Arnauld Sergé: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM U1068, CNRS UMR7258, Aix-Marseille Université UM105
Saidi M’Homa Soudja: Cancer Research Center of Lyon (CRCL) UMR INSERM1052
Julien C. Marie: Cancer Research Center of Lyon (CRCL) UMR INSERM1052

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13456-z

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