Dual roles for LUBAC signaling in thymic epithelial cell development and survival

Thymic epithelial cells (TECs) form a unique microenvironment that orchestrates T cell differentiation and immunological tolerance. Despite the importance of TECs for adaptive immunity, there is an incomplete understanding of the signalling networks that support their differentiation and survival. W...

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Published in:Cell death and differentiation 2021-10, Vol.28 (10), p.2946-2956
Main Authors: Jain, Reema, Zhao, Kelin, Sheridan, Julie M, Heinlein, Melanie, Kupresanin, Fiona, Abeysekera, Waruni, Hall, Cathrine, Rickard, James, Bouillet, Philippe, Walczak, Henning, Strasser, Andreas, Silke, John, Gray, Daniel H D
Format: Article
Language:English
Subjects:
Adaptive immunity
AIRE protein
Animals
Apoptosis
Atrophy
Cancer
Caspase-8
Cell activation
Cell differentiation
Cell Differentiation - physiology
Cell survival
Cell Survival - physiology
Epithelial cells
Epithelial Cells - cytology
Epithelial Cells - metabolism
Flow cytometry
Immunological tolerance
Immunology
Lymphocytes
Lymphocytes T
Medical research
Medulla oblongata
Mice
Mice, Inbred C57BL
Microenvironments
Mutation
Necroptosis
NF-κB protein
Proteins
Signal Transduction
Thymus
Thymus Gland - cytology
Thymus Gland - metabolism
Tumor necrosis factor-TNF
Ubiquitin
Ubiquitin - metabolism
Ubiquitination
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Summary:Thymic epithelial cells (TECs) form a unique microenvironment that orchestrates T cell differentiation and immunological tolerance. Despite the importance of TECs for adaptive immunity, there is an incomplete understanding of the signalling networks that support their differentiation and survival. We report that the linear ubiquitin chain assembly complex (LUBAC) is essential for medullary TEC (mTEC) differentiation, cortical TEC survival and prevention of premature thymic atrophy. TEC-specific loss of LUBAC proteins, HOIL-1 or HOIP, severely impaired expansion of the thymic medulla and AIRE-expressing cells. Furthermore, HOIL-1-deficiency caused early thymic atrophy due to Caspase-8/MLKL-dependent apoptosis/necroptosis of cortical TECs. By contrast, deficiency in the LUBAC component, SHARPIN, caused relatively mild defects only in mTECs. These distinct roles for LUBAC components in TECs correlate with their function in linear ubiquitination, NFκB activation and cell survival. Thus, our findings reveal dual roles for LUBAC signaling in TEC differentiation and survival.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-021-00850-8