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

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

doi:10.1038/ncomms13353

Abstract

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 homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.

Highlights

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear
The numbers, proportions and activation status of conventional CD8 þ and CD4 þ T cells in Sharpincpdm mice were comparable to controls (Fig. 1a–d)
These data indicate that the LUBAC components HOIL-1 and HOIP are necessary for conventional CD4 þ and CD8 þ T-cell differentiation, and that SHARPIN is dispensable

Summary

Introduction

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Innate and adaptive immune responses depend on LUBAC activity downstream of TNFR1, NOD2, TLR, NLRP3, TCR and B-cell receptor ligation[13,14]. These signals involve the linear ubiquitination of NEMO to reinforce canonical NF-kB signalling, it is likely to be that other LUBAC substrates exist. HOIP deficiency alone completely ablates LUBAC activity[18,19], SHARPIN-deficient cells still display substantial linear ubiquitination, because HOIL/HOIP complexes are able to sustain significant LUBAC function[17,18,19] Consistent with these observations, HOIP-deficient mice are embryonic lethal[18], whereas the SHARPIN-deficient mice from the chronic proliferative dermatitis mutation (cpdm) strain (hereafter referred to as Sharpincpdm mice) are born viable, but succumb to severe dermatitis at 12–14 weeks of age[20,21]

Methods

Results

Conclusion