The NF-κB RelA Transcription Factor Is Critical for Regulatory T Cell Activation and Stability

Ronin, Émilie; Ricco, Martina Lubrano di; Vallion, Romain; Divoux, Jordane; Kwon, Ho-Keun; Grégoire, Sylvie; Collares, Davi; Rouers, Angéline; Baud, Véronique; Benoist, Christophe; Salomon, Benoı̂t L.

doi:10.3389/fimmu.2019.02487

Cited by 45 publications

(35 citation statements)

References 59 publications

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“…It has been demonstrated that TNFR family co-stimulation increases regulatory T cell activation and function via NF-κB [ 62 ]. Moreover, it was shown that the NF-κB RelA subunit (p65) transcription factor is critical for T reg activation and stability [ 63 ]. This could explain why TNFR2 KO-MSCs maintain a certain level of immunoregulation and are still able to induce T regs.…”

Section: Discussionmentioning

confidence: 99%

TNFα/TNFR2 signaling pathway: an active immune checkpoint for mesenchymal stem cell immunoregulatory function

et al. 2020

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Background: In addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation. MSCs have the ability to modulate the immune response and change the progression of different inflammatory and autoimmune disorders. However, there are still many challenges to overcome before their widespread clinical administration including the mechanisms behind their immunoregulatory function. MSCs inhibit effector T cells and other immune cells, while inducing regulatory T cells (T regs), thus, reducing directly and indirectly the production of pro-inflammatory cytokines. TNF/TNFR signaling plays a dual role: while the interaction of TNFα with TNFR1 mediates pro-inflammatory effects and cell death, its interaction with TNFR2 mediates anti-inflammatory effects and cell survival. Many immunosuppressive cells like T regs, regulatory B cells (B regs), endothelial progenitor cells (EPCs), and myeloid-derived suppressor cells (MDSCs) express TNFR2, and this is directly related to their immunosuppression efficiency. In this article, we investigated the role of the TNFα/TNFR2 immune checkpoint signaling pathway in the immunomodulatory capacities of MSCs. Methods: Co-cultures of MSCs from wild-type (WT) and TNFR2 knocked-out (TNFR2 KO) mice with T cells (WT and TNFα KO) were performed under various experimental conditions. Results: We demonstrate that TNFR2 is a key regulatory molecule which is strongly involved in the immunomodulatory properties of MSCs. This includes their ability to suppress T cell proliferation, activation, and pro-inflammatory cytokine production, in addition to their capacity to induce active T regs. Conclusions: Our results reveal for the first time the importance of the TNFα/TNFR2 axis as an active immune checkpoint regulating MSC immunological functions.

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Section: Discussionmentioning

confidence: 99%

TNFα/TNFR2 signaling pathway: an active immune checkpoint for mesenchymal stem cell immunoregulatory function

et al. 2020

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“…Foxp3‐CRE‐IRES‐YFP ( Foxp3 Cre ) [50] and Foxp3‐IRES‐GFP [51] ( Foxp3 GFP ) knock‐in mice were kindly given by Prs. Alexander Rudensky and Bernard Malissen, respectively, and Rela flox knock‐in mice were previously described [52]. Foxp3‐DTR ( Foxp3 tm3(DTR/GFP)Ayr/J ), Tnf −/− ( Tnf tm1Gk1/J ), and Tnfrsf1b −/− ( Tnfrsf1 btm1Mwm/J ) were obtained from the Jackson laboratory.…”

Section: Methodsmentioning

confidence: 99%

“…RelA‐deficient Tregs and their control Tregs were similarly purified from Foxp3 Cre/+ x Rela flox and Foxp3 Cre/+ mice, respectively. We used Foxp3 Cre/+ x Rela flox mice because they did not develop autoimmunity, contrary to Foxp3 Cre x Rela flox mice as we recently reported [52].…”

Section: Methodsmentioning

confidence: 99%

Tumor necrosis factor receptor family costimulation increases regulatory T‐cell activation and function via NF‐κB

et al. 2020

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Several drugs targeting members of the TNF superfamily or TNF receptor superfamily (TNFRSF) are widely used in medicine or are currently being tested in therapeutic trials. However, their mechanism of action remains poorly understood. Here, we explored the effects of TNFRSF co-stimulation on murine Foxp3 + regulatory T cell (Treg) biology, as they are pivotal modulators of immune responses. We show that engagement of TNFR2, 4-1BB, GITR, and DR3, but not OX40, increases Treg proliferation and survival. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF-κB. Importantly, TNFRSF co-stimulation improves the ability of Tregs to suppress colitis. Our data demonstrate that stimulation of discrete TNFRSF members enhances Treg activation and function through a shared mechanism. Consequently, therapeutic effects of drugs targeting TNFRSF or their ligands may be mediated by their effect on Tregs.

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“…76 It is demonstrated that TNFR family co-stimulation increases Treg activation and function via NF-κB. 77,78 This could explain why priming ECFCs with 1 ng/ml of TNFα could still increase ECFC immunoregulatory effect. Apparently, this cross talk might be in an undemocratic manner since TNFR2 seems to govern the nal fate of TNFα signaling cascade.…”

Section: Several Studies Reported That Immunosuppressive Effect Of Vementioning

confidence: 99%

TNFα priming through its interaction with TNFR2 enhances Endothelial Progenitor Cell immunosuppressive effect: new hope for their widespread clinical application

Barkestani

Shamdani

Bakshloo

et al. 2020

Preprint

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Background: Bone marrow (BM) derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNFα is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNFα-TNFR2 dependent. Here, we aimed to investigate if an adequate TNFα pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions.Methods: EPCs were pre-treated with several doses of TNFα to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNFα priming would increase EPC immunosuppressive and immunomodulatory effect.Results: Treating EPCs with 1 ng/ml TNFα significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNFα priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNFα treatment led to the TNFα-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions.Conclusions: We report for the first time the crucial impact of inflammation notably the TNFα-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNFα-TNFR1 axis and, inversely the anti-inflammatory implication of the TNFα-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNFα prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs’ longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration.

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The NF-κB RelA Transcription Factor Is Critical for Regulatory T Cell Activation and Stability

Cited by 45 publications

References 59 publications

TNFα/TNFR2 signaling pathway: an active immune checkpoint for mesenchymal stem cell immunoregulatory function

TNFα/TNFR2 signaling pathway: an active immune checkpoint for mesenchymal stem cell immunoregulatory function

Tumor necrosis factor receptor family costimulation increases regulatory T‐cell activation and function via NF‐κB

TNFα priming through its interaction with TNFR2 enhances Endothelial Progenitor Cell immunosuppressive effect: new hope for their widespread clinical application

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