miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

Lu, Yunjie; Hippen, Keli L.; Lemire, Amanda L.; Gu, Jian; Wang, Weizhi; Ni, Xiao; Ranganathan, Parvathi; Levine, Bruce L.; Riley, James L.; June, Carl H.; Turka, Laurence A.; Munn, David H.; Garzon, Ramiro; Lü, Ling; Blazar, Bruce R.

doi:10.1182/blood-2016-05-714535

“…1A). Our previous study determined that miRNA-146b-5p increased TRAF6 expression in human tTregs (24). We further found that nTregs freshly isolated from human peripheral blood expressed TRAF6 mRNA to a greater degree than their non-Treg CD4+ counterparts ( Fig.Fig.…”

Section: Resultsmentioning

confidence: 58%

“…We found that by antagonizing a specific microRNA (miR-146b), which targets TRAF6 transcript, they could enhance Foxp3 protein levels. Moreover, the in vitro and in vivo function of Tregs could be enhanced through a miR-146b antagomir (24). Interestingly, while increased Additionally, it now appreciated that Foxp3 function is largely facilitated by a number of coregulator molecules such as Eos, IRF-4, GATA-3, and other members of the Foxp3 "interactome" (4)(5)(6)40).…”

Section: Discussionmentioning

confidence: 99%

TRAF6 directs Foxp3 localization and facilitates Treg function through K63-type ubiquitination

Ni

¹

,

Tao

²

,

Gu

³

et al. 2018

Preprint

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Regulatory T cells (Tregs) are crucial mediators of immune control. The characteristic gene expression and suppressive functions of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. Transcriptional regulation of the Foxp3 gene has been studied in depth, but both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. Here, we found that TRAF6‐deficient Tregs were dysfunctional in vivo; mice with Treg‐restricted deletion of TRAF6 were resistant to implanted tumors and displayed enhanced anti‐tumor immunity. We further determined that FOXP3 undergoes K63‐linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. In the absence of TRAF6 activity or upon mutation of the ubiquitination site, FOXP3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63‐linked ubiquitination by TRAF6 ensures proper localization of FOXP3 and facilitates the transcription factor's gene‐regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg‐stabilizing regulator that may be targeted in novel tolerance‐breaking therapies.

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“…Moreover, the in vitro and in vivo function of Tregs could be bolstered through treatment with a miR-146b antagomir (Lu et al, 2016). Particularly, we found that by antagonizing a specific microRNA (miR-146b), which targets TRAF6 transcript, Foxp3 protein levels could be enhanced.…”

Section: Discussionmentioning

confidence: 86%

“…Particularly, we found that by antagonizing a specific microRNA (miR-146b), which targets TRAF6 transcript, Foxp3 protein levels could be enhanced. Moreover, the in vitro and in vivo function of Tregs could be bolstered through treatment with a miR-146b antagomir (Lu et al, 2016). It should be pointed out that this prior study attributed increased FOXP3 expression and Treg function to elevated NFjB activity, which can drive transcription of the Foxp3 gene (Chiffoleau et al, 2003;Long et al, 2009), but levels of Foxp3 mRNA were not specifically measured.…”

Section: Discussionmentioning

confidence: 92%

TRAF 6 directs FOXP 3 localization and facilitates regulatory T‐cell function through K63‐linked ubiquitination

Ni

¹

,

Kou

²

,

Gu

³

et al. 2019

Self Cite

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Regulatory T cells (Tregs) are crucial mediators of immune control. The characteristic gene expression and suppressive functions of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. Transcriptional regulation of the Foxp3 gene has been studied in depth, but both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. Here, we found that TRAF6‐deficient Tregs were dysfunctional in vivo; mice with Treg‐restricted deletion of TRAF6 were resistant to implanted tumors and displayed enhanced anti‐tumor immunity. We further determined that FOXP3 undergoes K63‐linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. In the absence of TRAF6 activity or upon mutation of the ubiquitination site, FOXP3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63‐linked ubiquitination by TRAF6 ensures proper localization of FOXP3 and facilitates the transcription factor's gene‐regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg‐stabilizing regulator that may be targeted in novel tolerance‐breaking therapies.

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“…In an autoimmune setting, miR-146a expression can be induced by TNF-α (47), which in turn is stimulated by NF-κB, thus further confounding this complex regulatory network (Figure 4). Interestingly, another member of the miR-146 family, i.e., miR-146b, is highly expressed in CD4 + CD25 + FOXP3 + thymic-derived T regs and has been reported to promote survival, proliferation, and suppressor function of these cells by targeting TRAF6 and subsequently increasing NF-κB activity (54). …”

Section: Examples Of Snp–mrna–mirna Regulatory Network Controlling Omentioning

confidence: 99%

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

Gam

¹

,

Shah²,

Crossland

³

et al. 2017

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The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP–mRNA–miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.

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miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

Abstract: Key Points tTregs express high miR-146b levels and downregulate TRAF6 mRNA and NF-κB activation, which is essential for tTreg function. miR-146b antagomir enhances in vitro and in vivo tTreg suppression and persistence as well as xenogenic GVHD lethality.

Cited by 58 publications

References 69 publications

TRAF6 directs Foxp3 localization and facilitates Treg function through K63-type ubiquitination

TRAF6 directs Foxp3 localization and facilitates Treg function through K63-type ubiquitination

TRAF 6 directs FOXP 3 localization and facilitates regulatory T‐cell function through K63‐linked ubiquitination

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

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