A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell–mediated suppression

Song, Xin; Evel-Kabler, Kevin; Shen, Lei; Rollins, Lisa; Huang, Xue F.; Chen, Si-Yi

doi:10.1038/nm1721

Cited by 158 publications

(168 citation statements)

References 44 publications

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“…Recently, Song et al (40) silenced A20 in mouse DCs and demonstrated that this down-regulation results in up-regulation of different cell surface Ags associated with DC activation and the increased production of IL-6, IL-12p40 and TNF-␣ even in the absence of an activation stimulus. This is in contrast with our observations and our view on the role of A20, as a brake on TLR activation, in DCs.…”

Section: Discussionmentioning

confidence: 99%

Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine

Breckpot

Aerts-Toegaert

Heirman

et al. 2009

The Journal of Immunology

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A20 is a zinc finger protein with ubiquitin-modifying activity. A20 has been described as negatively regulating signaling induced by the TNF receptor and TLR family in a number of cell types, including mouse bone marrow-derived dendritic cells (DCs). However, the expression and effect of A20 in activated human monocyte-derived DCs have not been previously evaluated. We report that DCs activated with the TLR3 ligand poly(I:C) up-regulate A20. Down-regulating A20 demonstrated its role in the functional activation of DCs. A20 down-regulated DCs showed higher activation of the transcription factors NF-κB and activator protein-1, which resulted in increased and sustained production of IL-6, IL-10, and IL-12p70. We additionally silenced the immunosuppressive cytokine IL-10 and demonstrated that IL-10 inhibits T cell proliferation. We further demonstrated that A20 down-regulated DCs skew naive CD4+ T cells toward IFN-γ producing Th1 cells, a process which is dependent on IL-12p70 and which is unaffected by IL-10. Furthermore, A20 and/or IL-10 down-regulated DCs had an enhanced capacity to prime Melan-A/MART-1 specific CD8+ T cells. Finally, we demonstrated that potent T cell stimulatory DCs are generated by the simultaneous delivery of poly(I:C12U), A20, or A20/IL-10 small interfering RNA and Ag-encoding mRNA, introducing a one step approach to improve DC-based vaccines. Together these findings demonstrate that A20 negatively regulates NF-κB and activator protein-1 in DCs and that down-regulation of A20 results in DCs with enhanced T cell stimulatory capacity.

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Section: Discussionmentioning

confidence: 99%

Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine

Breckpot

Aerts-Toegaert

Heirman

et al. 2009

The Journal of Immunology

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“…Gene silencing of SOCS1 or A20 in DC was observed at a siRNA dose of 80 nM, whereas the efficiency of gene silencing was only modest (40-70%) [15,16]. On the other hand, a viral vector achieved more than 80% gene silencing [3,4]. Based on these findings, it is clear that a breakthrough delivery system is needed for the efficient introduction of siRNA to DCs.…”

Section: Introductionmentioning

confidence: 94%

“…RNAi technology can selectively control the expression of target molecules, resulting in the strict control of DC functions. Gene silencing of negative-feedback factors in DCs, such as the suppressor of cytokine signaling 1 (SOCS1) and A20, would be expected to greatly stimulate cytokine production and antitumor activity [3,4]. In addition to improving the strength of immunity mediated by DCs, gene silencing of the transforming growth factor β (TGF-β) receptor in DCs can result in the prevention of tumor-associated immunosuppression, because DC functions are also suppressed by TGF-β in a tumor microenvironment [5].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells

Warashina

Nakamura

Sato

et al. 2016

Journal of Controlled Release

104

102

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Applying small interfering RNA (siRNA) to dendritic cell (DC) based therapy excess of 90%, with a median effective dose (ED50) of 1.5 nM, whereas the maximum gene silencing efficiency of Lipofectamine RNAi MAX was less than 60% and the EC50 was 25 nM. Furthermore, a suppressor of cytokine signaling 1, an immune suppressive molecule in DCs, silenced in the mouse DC by the YSK12-MEND showed a drastic enhancement in cytokine production, resulting in the significant suppression of tumor growth when it was applied to DC-based therapy against a mouse lymphoma. These results clearly indicate that YSK12-MEND overcomes the obstacle associated with non-viral vectors and can be considered to be a promising non-viral vector for siRNA 2 delivery to DCs, thus accelerating DC-based therapies with siRNA.

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“…A20 knockdown in dendritic cells results in enhanced expression of specific co-stimulatory signals as well as pro-inflammatory cytokines, causing a shift in the subset of activated T cells. Both cytotoxic T cells and T helper cells were hyperactivated, whereas regulatory T cells were markedly suppressed, with beneficial anti-tumor effects as a result (10).…”

Section: Inhibitory Effect Of A20 On Pro-inflammatory Gene Expressionmentioning

confidence: 99%

A20: Central Gatekeeper in Inflammation and Immunity

Coornaert

Carpentier

Beyaert

2009

Journal of Biological Chemistry

291

253

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Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-B, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-B-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-B signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity. A20 (also known as TNFAIP3) was originally identified as a TNF 2 -inducible gene in human umbilical vein endothelial cells (1). Subsequent research demonstrated that A20 is also induced in many other cell types and by a wide range of other stimuli (reviewed in Ref. 2). Although A20 was originally characterized as an inhibitor of TNF-induced apoptosis (3), it has been most intensively studied as an inhibitor of NF-B activation. NF-B is a dimeric transcription factor that plays a key role in inflammation and immunity. A deregulated NF-B response has been associated with several autoimmune diseases and some cancers (4). The activity of NF-B is tightly regulated by interaction with inhibitory IB (inhibitor of B) proteins, which are regulated by IKK-mediated IB phosphorylation, followed by their ubiquitination and proteolysis, enabling the entry of NF-B into the nucleus. In most cases, the activation of NF-B is transient and cyclic upon continuous stimulation, which is due to specific negative feedback control systems such as the NF-Binducible synthesis of IB and A20 proteins (5). NF-B activation pathways are broadly classified as either canonical or noncanonical, depending on whether activation involves IB degradation or processing of the p100 NF-B precursor (4).The canonical pathway, which is the predominant NF-B signaling pathway, is activated by pro-inflammatory cytokines such as TNF and IL-1 and microbial components that activate, for example, TLRs or antigen receptors. The non-canonical pathway of NF-B activation operates mainly in B cells in response to a subset of TNFR family members, including the lymphotoxin-␤ receptor.Initial evidence for the NF-B inhibitory function of A20 came from several studies in which overexpression of A20 was shown to prevent NF-B activation in response to TNF and several other pro-inflammatory stimuli (reviewed in Ref.2). The observation that A20 expression is itself under the control of NF-B suggested its involvement in the negative feedback regulation of NF-B activation (6). This was eventually confirmed by the generation of A20-deficient mice, which show a sustained NF-B response and severe inflammation (7). The mechanism by which A20 inhibits NF-B activation remained a mystery for several years until it was recently found that A20 can act as a dual ubiquitin-editing enzyme.

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A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell–mediated suppression

Cited by 158 publications

References 44 publications

Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine

Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine

A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells

A20: Central Gatekeeper in Inflammation and Immunity

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