Journal article

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

Charis E Teh, Najoua Lalaoui, Reema Jain, Antonia N Policheni, Melanie Heinlein, Silvia Alvarez-Diaz, Julie M Sheridan, Eva Rieser, Stefanie Deuser, Maurice Darding, Hui-Fern Koay, Yifang Hu, Fiona Kupresanin, Lorraine A O'Reilly, Dale I Godfrey, Gordon K Smyth, Philippe Bouillet, Andreas Strasser, Henning Walczak, John Silke Show all



The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeosta..

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Awarded by Australian NHMRC grants

Awarded by Cancer Australia

Awarded by Leukemia and Lymphoma Society (SCOR grant)

Awarded by Australian Research Council (ARC)

Awarded by Wellcome Trust Senior Investigator Award

Awarded by ERC Advanced grant

Funding Acknowledgements

We thank D. Littman, A. Rudensky, W. Alexander, H. Korner, V. Dixit, C. Thomson, S. Korsmeyer, D. Green, K. Rajewsky and S. Hendrick for provision of mice. We are grateful to the Bioservices staff of WEHI for mouse husbandry, B. Helbert, C. Young and K. Mackwell for genotyping, A. Lin and S. Wilcox for technical assistance, and P. Savage for providing a-GalCer (PBS-44) for CD1d tetramer studies. This work was funded by Australian NHMRC grants (Project and Program Grants 1078763, 1049724, 1083942, 1013667, 1016701, 1046010, 602516, 104984, 1057905 and 1058190; Fellowships 1089072 for C.E.T., 1090236 for D.H.D.G. and 1020770 for D.I.G.), Cancer Australia (1047672), Leukemia and Lymphoma Society (SCOR grant 7413 and 7001-13), the Australian Research Council (ARC) CE140100011 and LE110100106, a Wellcome Trust Senior Investigator Award (096831/Z/11/Z for H.W.) and ERC Advanced grant (294880 for H.W.). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.