A20 Restrains Thymic Regulatory T Cell Development

Fischer, Julius; Otten, Vera; Kober, Maike; Drees, Christoph; Rosenbaum, Marc; Schmickl, Martina; Heidegger, Simon; Beyaert, Rudi; Loo, Geert; Li, Xian Chang; Peschel, Christian; Schmidt-Supprian, Marc; Haas, Tobias; Spoerl, Silvia; Poeck, Hendrik

doi:10.4049/jimmunol.1602102

Cited by 35 publications

(21 citation statements)

References 55 publications

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“…Differences in T-cell-specific Tnfaip3 deletion between the two mouse strains could indicate that either CD8 + T-cells drive inflammation in Tnfaip3 maT-KO mice or CD4 + T-cells have increased regulatory function in Tnfaip3 CD4-KO mice. Indeed, regulatory T cell (Treg) proportions were increased in Tnfaip3 CD4-KO mice, because of a reduced IL-2 dependence for their development ( 93 ). In vitro activated CD4 + T-cells from Tnfaip3 CD4-KO mice died quicker than wild-type T-cells ( 14 , 15 ), due to A20/TNFAIP3’s control on necroptosis ( 14 ) and autophagy ( 15 ).…”

Section: Immune Cell-specific Deletion Of A20/ Tnfaip3 mentioning

confidence: 99%

A20/Tumor Necrosis Factor α-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models

Das¹,

Chen²,

Hendriks³

et al. 2018

Front. Immunol.

144

106

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Immune cell activation is a stringently regulated process, as exaggerated innate and adaptive immune responses can lead to autoinflammatory and autoimmune diseases. Perhaps the best-characterized molecular pathway promoting cell activation is the nuclear factor-κB (NF-κB) signaling pathway. Stimulation of this pathway leads to transcription of numerous pro-inflammatory and cell-survival genes. Several mechanisms tightly control NF-κB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor α-induced protein 3 (TNFAIP3). Single nucleotide polymorphisms (SNPs) in the vicinity of the TNFAIP3 gene are associated with a spectrum of chronic systemic inflammatory diseases, indicative of its clinical relevance. Mice harboring targeted cell-specific deletions of the Tnfaip3 gene in innate immune cells such as macrophages spontaneously develop autoinflammatory disease. When immune cells involved in the adaptive immune response, such as dendritic cells or B-cells, are targeted for A20/TNFAIP3 deletion, mice develop spontaneous inflammation that resembles human autoimmune disease. Therefore, more knowledge on A20/TNFAIP3 function in cells of the immune system is beneficial in our understanding of autoinflammation and autoimmunity. Using the aforementioned mouse models, novel A20/TNFAIP3 functions have recently been described including control of necroptosis and inflammasome activity. In this review, we discuss the function of the A20/TNFAIP3 enzyme and its critical role in various innate and adaptive immune cells. Finally, we discuss the latest findings on TNFAIP3 SNPs in human autoinflammatory and autoimmune diseases and address that genotyping of TNFAIP3 SNPs may guide treatment decisions.

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Section: Immune Cell-specific Deletion Of A20/ Tnfaip3 mentioning

confidence: 99%

A20/Tumor Necrosis Factor α-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models

Das¹,

Chen²,

Hendriks³

et al. 2018

Front. Immunol.

144

106

View full text Add to dashboard Cite

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“…The Treg frequency is enhanced although Tregs are less functional than the wild-type counterparts ( 44 ). Recently, it was demonstrated that another negative regulator of NF-κB—ubiquitin-editing enzyme A20—restricts nTreg development; however, A20-/- Tregs are completely functional in vivo ( 45 ). Interestingly, while A20 terminates NF-κB signaling, CYLD prevents spontaneous NF-κB activation.…”

Section: The Nf-κb Team In Treg Biologymentioning

confidence: 99%

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

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“…Consistent with this, A20-deficient mice are hypersensitive to TNF exposure and die perinatally because of severe inflammation and multiorgan failure [42]. Intriguingly, A20 is recently shown to regulate the de novo generation of tTreg in a cell-intrinsic manner, while the suppressor function of A20-deficient Treg is unchanged in vitro [43].…”

Section: Tnf/tnfr Signaling Pathwaysmentioning

confidence: 74%

TNFR2 and Regulatory T Cells: Potential Immune Checkpoint Target in Cancer Immunotherapy

He¹,

Wang²

2020

Cytokines

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TNF has both proinflammatory and antiinflammatory effects. It binds to two structurally related but functionally distinct receptors TNFR1 and TNFR2. Unlike TNFR1 that is ubiquitously expressed, TNFR2 expression is more limited to myeloid and lymphoid cell lineages including a fraction of regulatory T cells (Treg). In general, TNFR1 is responsible for TNF-mediated cell apoptosis and death, and mostly induces proinflammatory reactions. However, TNFR2 mainly leads to functions related to cell survival and immune suppression. Treg play an indispensable role in maintaining immunological self-tolerance and restraining excessive immune reactions deleterious to the host. Impaired Treg-mediated immune regulation has been observed in various autoimmune diseases as well as in cancers. Therefore, Treg might provide an ideal therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. TNFR2 is highly expressed on Treg in mice and in humans, and TNFR2+ Treg reveal the most potent suppressive capacity. TNF-TNFR2 ligation benefits Treg proliferation, although the effect on Treg suppressive function remains controversial. Here, we will describe in detail the TNF-mediated regulation of Treg and the potential clinical applications in cancer immunotherapy as well as in autoimmune diseases, with the focus on human Treg subsets.

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A20 Restrains Thymic Regulatory T Cell Development

Cited by 35 publications

References 55 publications

A20/Tumor Necrosis Factor α-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models

A20/Tumor Necrosis Factor α-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

TNFR2 and Regulatory T Cells: Potential Immune Checkpoint Target in Cancer Immunotherapy

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