A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

Just, Sissy; Nishanth, Gopala; Buchbinder, Jörn H.; Wang, Xu; Naumann, Michael; Lavrik, Inna N.; Schlüter, Dirk

doi:10.1038/srep39796

Cited by 26 publications

(17 citation statements)

References 59 publications

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“…We thus propose that during conditioning therapy for allo‐HSCT, A20‐deficient T cells are primed by activated donor APCs, triggering their activation but also their cell death. This is in line with recent reports indicating that A20 restricts necroptosis and apoptosis after activation of CD4 + and CD8 + T cells . Reduced survival after TCR‐ and co‐stimulation may thus contribute to reduced T‐cell fractions in naïve CD4 A20 −/− mice.…”

Section: Discussionsupporting

confidence: 92%

“…The increased percentage of IFN‐γ‐producing T cells after allo‐HSCT suggested that A20‐deficient T cells were especially prone to activation due to failing negative feedback regulation of NF‐κB, consistent with enhanced CD8 + T cell effector function of A20‐deficient T cells . However, increased early T cell activation with transitorily enhanced local and systemic inflammation is not enduring due to higher susceptibility to cell death, otherwise intrinsically detained by A20.…”

Section: Discussionmentioning

confidence: 90%

“…However, the role of A20 in T cells and T‐cell‐mediated diseases is only beginning to emerge. In CD8 + T cells, deletion of A20 led to increased production of pro‐inflammatory cytokines such as IFN‐γ, TNF and IL‐2 but resulted in enhanced cell death and impaired memory T‐cell responses . In CD4 + T cells, A20 was shown to be essential for survival and expansion by promoting autophagy and protecting from necroptotic cell death .…”

Section: Introductionmentioning

confidence: 99%

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A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

et al. 2017

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The NF-κB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4 and CD8 donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-γ and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20 T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20 T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

et al. 2017

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“…2e ). This finding is in agreement with the concept that A20 functions to prevent cell death that could occur due to apoptosis and necroptosis 33 – 35 . To study the effect of A20 deficiency in ECs on LPS-induced lung vascular permeability, we first measured the pulmonary vascular liquid filtration coefficient ( K f,c ) using isolated lung preparations of both genotypes.…”

Section: Resultssupporting

confidence: 92%

Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury

Soni

Wang

Regmi

et al. 2018

Cell Death Discovery

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Vascular endothelial cadherin (VE-cad) expression at endothelial adherens junctions (AJs) regulates vascular homeostasis. Here we show that endothelial A20 is required for VE-cad expression at AJs to maintain and repair the injured endothelial barrier. In endothelial cell (EC)-restricted Tnfaip3 (A20) knockout (A20∆EC) mice, LPS challenge caused uncontrolled lung vascular leak and persistent sequestration of polymorphonuclear neutrophil (PMNs). Importantly, A20∆EC mice exhibited drastically reduced VE-cad expression in lungs compared with wild-type counterparts. Endothelial expression of wild-type A20 but not the deubiquitinase-inactive A20 mutant (A20C103A) prevented VE-cad ubiquitination, restored VE-cad expression, and suppressed lung vascular leak in A20∆EC mice. Interestingly, IRAK-M-mediated nuclear factor-κB (NF-κB) signaling downstream of TLR4 was required for A20 expression in ECs. interleukin-1 receptor-associated kinase M (IRAK-M) knockdown suppressed basal and LPS-induced A20 expression in ECs. Further, in vivo silencing of IRAK-M in mouse lung vascular ECs through the CRISPR-Cas9 system prevented expression of A20 and VE-cad while augmenting lung vascular leak. These results suggest that targeting of endothelial A20 is a potential therapeutic strategy to restore endothelial barrier integrity in the setting of acute lung injury.

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“…Increased necroptosis in A20/ Tnfaip3 -deficient CD4 + T-cells impaired Th1 and Th17-cell differentiation in vitro ( 14 ). Interestingly, perinatal death of Tnfaip3 KO mice was greatly delayed by RIPK3 deficiency, implying that A20/TNFAIP3 may control necroptosis in other cell types ( 14 ), such as CD8 + T-cells ( 95 ). Preventing necroptosis did not fully restore survival of A20/ Tnfaip3 -deficient CD4 + T-cells ( 14 ), which could be attributed to autophagy, a lysosomal degradation pathway necessary for survival after TCR stimulation ( 96 ).…”

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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A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

Cited by 26 publications

References 59 publications

A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury

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

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