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Nat Commun. 2019 Dec 19;10(1):5690. doi: 10.1038/s41467-019-13456-z.

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

McCarron MJ1,2,3,4,5, Irla M6, Sergé A7, Soudja SM1,2,3,4, Marie JC8,9,10,11.

Author information

1
Department of Immunology Virology and Inflammation, Cancer Research Center of Lyon (CRCL) UMR INSERM1052, CNRS 5286 28 rue Laennec, F-69373 cedex 08, Lyon, France.
2
Université Lyon 1, F-69000, Lyon, France.
3
Centre Léon Bérard, Lyon, F-69008, Lyon, France.
4
Labex DEVweCAN F-69008, Lyon, France.
5
Genentech, South San Francisco, CA, 94080, USA.
6
Centre d'Immunologie de Marseille Luminy (CIML), INSERM U1104, CNRS UMR 7280, Aix-Marseille Université UM2, F-13288 cedex 09, Marseille, France.
7
Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM U1068, CNRS UMR7258, Aix-Marseille Université UM105, 13273 cedex 09, Marseille, France.
8
Department of Immunology Virology and Inflammation, Cancer Research Center of Lyon (CRCL) UMR INSERM1052, CNRS 5286 28 rue Laennec, F-69373 cedex 08, Lyon, France. julien.marie@inserm.fr.
9
Université Lyon 1, F-69000, Lyon, France. julien.marie@inserm.fr.
10
Centre Léon Bérard, Lyon, F-69008, Lyon, France. julien.marie@inserm.fr.
11
Labex DEVweCAN F-69008, Lyon, France. julien.marie@inserm.fr.

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.

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