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

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

doi:10.1038/ncomms13353

Cited by 54 publications

(60 citation statements)

References 67 publications

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“…Hence, factors that affect thymocyte survival may impact on the development of MAIT cells as the gene encoding the MAIT TCR Vα‐chain (Vα19) is located at the extreme end of the 5′ end of the TCRα locus . Inhibitors of DNA transcription factors (Id2 and Id3), which interact with E proteins, have also been implicated in the development and differentiation of NKT cells, and more recently, we showed that members of the linear ubiquitin chain assembly complex, Hoil and Hoip, were required for normal NKT cell development in the thymus . Interestingly, the SLAM/SAP/Fyn pathway does not appear to be necessary for the development of MAIT cells, whereas it is important for the development of NKT cells .…”

Section: Factors That Regulate Mait Cell Developmentmentioning

confidence: 99%

“…60 Inhibitors of DNA transcription factors (Id2 and Id3), which interact with E proteins, have also been implicated in the development and differentiation of NKT cells, [61][62][63][64] and more recently, we showed that members of the linear ubiquitin chain assembly complex, Hoil and Hoip, were required for normal NKT cell development in the thymus. 65 Interestingly, the SLAM/ SAP/Fyn pathway does not appear to be necessary for the development of MAIT cells, whereas it is important for the development of NKT cells. 16,[66][67][68][69] The use of MR1 tetramers in candidate gene knockout mice should lead to the discovery of key molecules that are important for the development of MAIT cells and these can be compared with those that regulate the development of NKT cells.…”

Section: Factors That Regulate Mait Cell Developmentmentioning

confidence: 99%

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Development of mucosal‐associated invariant T cells

2018

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Mucosal-associated invariant T (MAIT) cells develop in the thymus and migrate into the periphery to become the largest antigen-specific αβ T-cell population in the human immune system. However, the frequency of MAIT cells varies widely between human individuals, and the basis for this is unclear. While MAIT cells are highly conserved through evolution and are phenotypically similar between humans and mice, they represent a much smaller proportion of total T cells in mice. In this review, we discuss how MAIT cells transition through a three-stage development pathway in both mouse and human thymus, and continue to mature and expand after they leave the thymus. Moreover, we will explore and speculate on how specific factors regulate different stages of this process.

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Section: Factors That Regulate Mait Cell Developmentmentioning

confidence: 99%

Section: Factors That Regulate Mait Cell Developmentmentioning

confidence: 99%

Development of mucosal‐associated invariant T cells

2018

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“…193,194 Recently, LUBAC activity has been reported to be required for late thymocyte differentiation, Treg development, and homeostasis, but was dispensable for the protection of Tregs against TNF-induced cell death. 195 On the other hand, deficiency for M1-deubiquitinase OTULIN leads to a severe spontaneous autoinflammation by T cell-specific NF-κB induction, as regulated cell death may not be activated properly. 196 It was thought that apoptosis might trigger the lethal phenotype of the TNFα-mediated shock and a study found the pan-caspase inhibitor zVAD-fmk to be protective in TNF-shock by inhibiting leukocyte apoptosis 199 ; however, later reports more reliably found that caspase inhibition by zVAD-fmk exacerbated the shock, resulting in TNF/ zVAD-mediated hyperacute shock.…”

Section: T-cell Function and Necroptosismentioning

confidence: 99%

The in vivo evidence for regulated necrosis

Tonnus

Linkermann

2017

Immunological Reviews

102

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Necrosis is a hallmark of several widespread diseases or their direct complications. In the past decade, we learned that necrosis can be a regulated process that is potentially druggable. RIPK3- and MLKL-mediated necroptosis represents by far the best studied pathway of regulated necrosis. During necroptosis, the release of damage-associated molecular patterns (DAMPs) drives a phenomenon referred to as necroinflammation, a common consequence of necrosis. However, most studies of regulated necrosis investigated cell lines in vitro in a cell autonomous manner, which represents a non-physiological situation. Conclusions based on such work might not necessarily be transferrable to disease states in which synchronized, non-cell autonomous effects occur. Here, we summarize the current knowledge of the pathophysiological relevance of necroptosis in vivo, and in light of this understanding, we reassess the morphological classification of necrosis that is generally used by pathologists. Along these lines, we discuss the paucity of data implicating necroptosis in human disease. Finally, the in vivo relevance of non-necroptotic forms of necrosis, such as ferroptosis, is addressed.

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“…Treg-specific HOIP ablation leads to lethal immune pathology in mice [96]. Furthermore, the HOIP-RBR region regulates T-cell and B-cell differentiation.…”

Section: Linear Ubiquitin Chains In the Regulation Of Immune And Cellmentioning

confidence: 99%

Linear ubiquitin chains: enzymes, mechanisms and biology

Rittinger

Ikeda

2017

Open Biol.

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Ubiquitination is a versatile post-translational modification that regulates a multitude of cellular processes. Its versatility is based on the ability of ubiquitin to form multiple types of polyubiquitin chains, which are recognized by specific ubiquitin receptors to induce the required cellular response. Linear ubiquitin chains are linked through Met 1 and have been established as important players of inflammatory signalling and apoptotic cell death. These chains are generated by a ubiquitin E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) that is thus far the only E3 ligase capable of forming linear ubiquitin chains. The complex consists of three subunits, HOIP, HOIL-1L and SHARPIN, each of which have specific roles in the observed biological functions of LUBAC. Furthermore, LUBAC has been found to be associated with OTULIN and CYLD, deubiquitinases that disassemble linear chains and counterbalance the E3 ligase activity of LUBAC. Gene mutations in HOIP, HOIL-1L and OTULIN are found in human patients who suffer from autoimmune diseases, and HOIL-1L mutations are also found in myopathy patients. In this paper, we discuss the mechanisms of linear ubiquitin chain generation and disassembly by their respective enzymes and review our current understanding of their biological functions and association with human diseases.

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

Cited by 54 publications

References 67 publications

Development of mucosal‐associated invariant T cells

Development of mucosal‐associated invariant T cells

The in vivo evidence for regulated necrosis

Linear ubiquitin chains: enzymes, mechanisms and biology

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