Suppressive activity of human regulatory T cells is maintained in the presence of TNF

Zaragoza, Bruno; Chen, Xin; Oppenheim, Joost J.; Baeyens, Audrey; Grégoire, Sylvie; Chader, Driss; Gorochov, Guy; Miyara, Makoto; Salomon, Benoı̂t L.

doi:10.1038/nm.4019

Cited by 90 publications

(88 citation statements)

References 13 publications

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“…This is consistent with previous data in the context of autoimmune diseases in mice 16 and with our recent findings that TNF increased Foxp3 expression in human Tregs in vitro. 27 These results shed light on the conflicting data regarding the effect of anti-TNF drugs. These agents are widely used in the treatment of various autoimmune diseases.…”

Section: Discussionmentioning

confidence: 92%

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Leclerc

Naserian

Pilon

et al. 2016

Blood

103

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Key Points• In vivo Treg effect depends on TNFa produced by T cells.• TNF/TNFR2 interaction represents a novel immune checkpoint therapy to modulate alloreactivity after allo-HCT. Therapeutic CD41 Foxp3 1 natural regulatory T cells (Tregs) can control experimental graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by suppressing conventional T cells (Tconvs). Treg-based therapies are currently tested in clinical trials with promising preliminary results in allo-HCT. Here, we hypothesized that as Tregs are capable of modulating Tconv response, it is likely that the inflammatory environment and particularly donor T cells are also capable of influencing Treg function. Indeed, previous findings in autoimmune diabetes revealed a feedback mechanism that renders Tconvs able to stimulate Tregs by a mechanism that was partially dependent on tumor necrosis factor (TNF). We tested this phenomenon during alloimmune response in our previously described model of GVHD protection using antigen specific Tregs. Using different experimental approaches, we observed that control of GVHD by Tregs was fully abolished by blocking TNF receptor type 2 (TNFR2) or by using TNF-deficient donor T cells or TNFR2-deficient Tregs. Thus, our results show that Tconvs exert a powerful modulatory activity on therapeutic Tregs and clearly demonstrate that the sole defect of TNF production by donor T cells was sufficient to completely abolish the Treg suppressive effect in GVHD. Importantly, our findings expand the understanding of one of the central components of Treg action, the inflammatory context, and support that targeting TNF/TNFR2 interaction represents an opportunity to efficiently modulate alloreactivity in allo-HCT to either exacerbate it for a powerful antileukemic effect or reduce it to control GVHD. (Blood. 2016;128(12):1651-1659

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Section: Discussionmentioning

confidence: 92%

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Leclerc

Naserian

Pilon

et al. 2016

Blood

103

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“…15,[18][19][20][21][22] Our models offer a unique perspective, demonstrating that brief TNF-a priming coupled with IL-2 stimulation can be used to improve cellular therapy with highly purified (FoxP3 $95%) mouse-derived Tregs in GVHD, and/or to minimize Tcons morbidity and lethality. Moreover, anti-TNF-a treatments are employed in GVHD and autoimmune diseases.…”

Section: Resultsmentioning

confidence: 99%

TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment

Pierini

Strober

Moffett

et al. 2016

Blood

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“…Interestingly, treatment with infliximab, an anti-TNF-α antibody, not only restored both Foxp3 phosphorylation and Treg cell activity, but also reduced PP1 expression as well as Th17 and Th1 cell numbers, thus altering the Treg/Th17 and Treg/Th1 cell ratio in favor of immune regulation. Contrary to the above study [119], it has been reported that TNF-α can enhance the expression of CD25 and FoxP3 in Treg cells co-cultured with IL-2 and TNF-α, and that Treg cells maintain their suppressive activity in the presence of TNF-α [117]. …”

Section: Tnf-α-induced Immune Regulationmentioning

confidence: 86%

“…On the contrary, treatment with TNF-α per se has been shown to be beneficial in animal models of autoimmunity, such as RA [38], lupus [110], and IDDM (T1D) [111]. In addition, there are conflicting reports on the influence of TNF-α on the generation and function of Treg cells [112, 113]; some reports emphasize a positive relationship between TNF-α and Treg cell expansion and/or function [112, 114–117], while others describe a negative effect of TNF-α on Treg cell number and activity [118–120]. There is additional disparity between murine and human Treg cells in regard to the effect of TNF-α on these cells [112, 113].…”

Section: Tnf-α-induced Immune Regulationmentioning

confidence: 99%

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

2017

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Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed a paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.

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Suppressive activity of human regulatory T cells is maintained in the presence of TNF

Cited by 90 publications

References 13 publications

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

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