<scp>SHARPIN</scp> controls the development of regulatory T cells

Redecke, Vanessa; Chaturvedi, V. N.; Kuriakose, Jeeba A.

doi:10.1111/imm.12604

Cited by 20 publications

(17 citation statements)

References 51 publications

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“…1a–d). Consistent with recent reports2526, we observed that Treg cells were reduced in Sharpin cpdm mice, although to a much lesser extent compared with the Hoip ΔCd4 and Hoil ΔCd4 mice (Fig. 1a,b).…”

Section: Resultssupporting

confidence: 93%

“…36) and our data showing that constitutive active IKK2 cannot restore peripheral T cells suggest that there are other LUBAC-dependent signals downstream of the TCR that are required for SP thymocyte maturation. Indeed, a role for SHARPIN has been implicated in JNK and ERK activation downstream of TCR signals2526. Another possibility is that LUBAC is required to transduce signals from other cell surface receptors critical for SP maturation, such as members of the TNFR superfamily.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Recent studies from two different groups have demonstrated T-cell intrinsic roles for SHARPIN, revealing a requirement for SHARPIN in regulatory T-cell development and function1920. Herein, our studies demonstrate that immune cell dysregulation precedes the development of dermatitis in Sharpin cpdm mice.…”

Section: Discussionsupporting

confidence: 51%

Distinct role of IL-1β in instigating disease in Sharpincpdm mice

Gurung

Sharma

Kanneganti

2016

Sci Rep

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Mice deficient in SHARPIN (Sharpincpdm mice), a member of linear ubiquitin chain assembly complex (LUBAC), develop severe dermatitis associated with systemic inflammation. Previous studies have demonstrated that components of the TNF-signaling pathway, NLRP3 inflammasome and IL-1R signaling are required to provoke skin inflammation in Sharpincpdm mice. However, whether IL-1α or IL-1β, both of which signals through IL-1R, instigates skin inflammation and systemic disease is not known. Here, we have performed extensive cellular analysis of pre-diseased and diseased Sharpincpdm mice and demonstrated that cellular dysregulation precedes skin inflammation. Furthermore, we demonstrate a specific role for IL-1β, but not IL-1α, in instigating dermatitis in Sharpincpdm mice. Our results altogether demonstrate distinct roles of SHARPIN in initiating systemic inflammation and dermatitis. Furthermore, skin inflammation in Sharpincpdm mice is specifically modulated by IL-1β, highlighting the importance of specific targeted therapies in the IL-1 signaling blockade.

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“…We and others showed that LUBAC plays a role in activating the canonical NF-kB pathway and inhibiting TNF-a-induced cell death (12)(13)(14)(15). The role of LUBAC during development and function of B and T lymphocytes has also been dissected (16,(27)(28)(29)(30). In B cells, LUBAC plays crucial roles in TD and TI-II Ab responses by controlling CD40and TACI-mediated activation of the canonical NF-kB and ERK pathways, respectively; it also regulates B1 cell development (16).…”

Section: Discussionmentioning

confidence: 99%

Crucial Role of Linear Ubiquitin Chain Assembly Complex–Mediated Inhibition of Programmed Cell Death in TLR4-Mediated B Cell Responses and B1b Cell Development

Sasaki

Iwaï

2018

The Journal of Immunology

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Linear ubiquitin chain assembly complex (LUBAC)-mediated linear polyubiquitin plays crucial roles in thymus-dependent and -independent type II Ab responses and B1 cell development. In this study, we analyzed the role of LUBAC in TLR-mediated B cell responses. A mouse strain in which LUBAC activity was ablated specifically in B cells (B-HOIP mice) showed defective Ab responses to a type I thymus-independent Ag, NP-LPS. B cells from B-HOIP mice (HOIP B cells) underwent massive cell death in response to stimulation of TLR4, but not TLR9. TLR4 stimulation induced caspase-8 activation in HOIP B cells; this phenomenon, as well as TLR4-induced cell death, was suppressed by ablation of TRIF, a signal inducer specific for TLR4. In addition, LPS-induced survival, proliferation, and differentiation into Ab-producing cells of HOIP B cells were substantially restored by inhibition of caspases together with RIP3 deletion, but not by RIP3 deletion alone, suggesting that LPS stimulation kills HOIP B cells by apoptosis elicited via the TRIF pathway. Further examination of the roles of cell death pathways in B-HOIP mice revealed that deletion of RIP3 increased the number of B1 cells, particularly B1b cells, in B-HOIP mice, indicating that B1b cell homeostasis is controlled via LUBAC-mediated suppression of necroptosis. Taken together, the data show that LUBAC regulates TLR4-mediated B cell responses and B1b cell development and/or maintenance by inhibiting programmed cell death.

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SHARPIN controls the development of regulatory T cells

Cited by 20 publications

References 51 publications

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

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

Distinct role of IL-1β in instigating disease in Sharpincpdm mice

Crucial Role of Linear Ubiquitin Chain Assembly Complex–Mediated Inhibition of Programmed Cell Death in TLR4-Mediated B Cell Responses and B1b Cell Development

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