期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13456-z
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资金
- Helmholtz-DKFZ-Inserm program
- Agence Nationale pour la Recherche (ANR) investissement d'avenir [ANR-10-LABX-61]
- foundation Schuller-Bettencourt
- Ligue Nationale Contre le Cancer labelisee, EL-2016, Marie Curie Career integration grant [CIG_ SIGnEPI4Tol_618541]
- Swiss National Science Foundation [PZ00P3 131945]
- Fondation pour la Recherche Medicale [SPF20110421356]
- Swiss National Science Foundation (SNF) [PZ00P3_131945] Funding Source: Swiss National Science Foundation (SNF)
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-beta) 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-beta in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.
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