Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF–TNF-RII binding in rheumatoid arthritis

Nguyen, D.; Ehrenstein, Michael R.

doi:10.1084/jem.20151255

Cited by 157 publications

(155 citation statements)

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“…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%

“…Additional insight into the impact of TNFR2 on Treg cell activity has been gained from a recent study on adalimumab, an humanized anti-TNF-α antibody [113]. Adalimumab can bind to the mTNF-α on monocytes of RA patients but not healthy controls [113].…”

Section: Tnf-α-induced Immune Regulationmentioning

confidence: 99%

“…Adalimumab can bind to the mTNF-α on monocytes of RA patients but not healthy controls [113]. This binding caused upregulation of mTNF-α on the monocytes and increased the interaction of monocytes with Treg cells through TNFR2 (Fig.…”

Section: Tnf-α-induced Immune Regulationmentioning

confidence: 99%

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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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Section: Tnf-α-induced Immune Regulationmentioning

confidence: 99%

Section: Tnf-α-induced Immune Regulationmentioning

confidence: 99%

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Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

2017

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“…However, a still incomplete understanding of the mechanism of TNFRSF signaling hampers the development of more effective therapies. For instance, it has only been recently established that TNF receptor II (TNFR2) is an important pathway of regulatory T cell (T reg ) expansion or contraction, even in adult human T cells (5)(6)(7). T regs are important targets for both cancer and autoimmune therapies, and there are several TNFRSF receptors expressed on T reg and other immune cells to regulate their function.…”

Section: Introductionmentioning

confidence: 99%

Structural principles of tumor necrosis factor superfamily signaling

2018

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The tumor necrosis factor (TNF) ligand and receptor superfamilies play an important role in cell proliferation, survival, and death. Stimulating or inhibiting TNF superfamily signaling pathways is expected to have therapeutic benefit for patients with various diseases, including cancer, autoimmunity, and infectious diseases. We review our current understanding of the structure and geometry of TNF superfamily ligands, receptors, and their interactions. A trimeric ligand and three receptors, each binding at the interface of two ligand monomers, form the basic unit of signaling. Clustering of multiple receptor subunits is necessary for efficient signaling. Current reports suggest that the receptors are prearranged on the cell surface in a "nonsignaling," resting state in a large hexagonal structure of antiparallel dimers. Receptor activation requires ligand binding, and cross-linking antibodies can stabilize the receptors, thereby maintaining the active, signaling state. On the other hand, an antagonist antibody that locks receptor arrangement in antiparallel dimers effectively blocks signaling. This model may aid the design of more effective TNF signaling-targeted therapies.

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“…2 Moreover, it has been shown that therapeutic TNF blockade with the anti-TNF monoclonal antibody adalimumab restores the potency of Treg cell suppression in RA by binding to membrane TNF-a on monocytes and promoting Treg cell expansion through enhanced TNFR2 signaling. 3 In the present study we aimed to establish the role of TNFR2 on Tregs in control of inflammation at multiple levels, by: 1) studying the action of TNF on Treg function in the presence and absence of TNFR2 in vitro, 2) testing the severity of a model of skin inflammation in TNFR2KO mice, 3) evaluating the evolution of TNFR2-expressing Treg from RA patients during anti-TNF treatment. Materials and methods Mice deficient in the TNFR2 gene (TNFR2 KO) and TNFR2 lox/lox mice to conditionally delete TNFR2 specifically in Tregs were used.…”

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confidence: 99%

03.12 Tnfr2⁺regulatory t cells subpopulations are highly suppressive and are increased on anti-tnf treatment

et al. 2017

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BackgroundIn rheumatoid arthritis (RA), regulatory T cells (Tregs) are defective in their suppressive capacities and fail to control chronic inflammation. TNF-α is involved in inhibition of Treg differentiation and activation, likely via activation of TNF type 1 receptor (TNFR1).1 Conversely, activation of TNFR2 on Tregs is critical for their phenotypic and functional stability in the inflammatory environment.2 Moreover, it has been shown that therapeutic TNF blockade with the anti-TNF monoclonal antibody adalimumab restores the potency of Treg cell suppression in RA by binding to membrane TNF- α on monocytes and promoting Treg cell expansion through enhanced TNFR2 signaling.3 In the present study we aimed to establish the role of TNFR2 on Tregs in control of inflammation at multiple levels, by: 1) studying the action of TNF on Treg function in the presence and absence of TNFR2 in vitro, 2) testing the severity of a model of skin inflammation in TNFR2KO mice, 3) evaluating the evolution of TNFR2-expressing Treg from RA patients during anti-TNF treatment.Materials and methodsMice deficient in the TNFR2 gene (TNFR2 KO) and TNFR2 lox/lox mice to conditionally delete TNFR2 specifically in Tregs were used. CD4+CD25+Treg cells were purified by magnetic sorting. Cell phenotype was evaluated by flow cytometry. ATP concentrations were determined by luminometry. Skin inflammation was induced by applying an imiquimod-containing ointment, to the skin. Peripheral blood Treg where characterised before and after 3 months of anti–TNF treatment in 10 RA patients.ResultsIn vitro, TNF-α enhanced Foxp3 maintenance through TNFR2 signalling in cultured Tregs. In vivo, TNFR2-negative Treg cells, from both TNFR2KO and TNFR2 lox/lox mice, had lower spontaneous suppressive capacities (lower ATP hydrolysis, inhibition of effector T cells proliferation and IFN-γ production). Compared to wt mice, TNFR2KO mice had enhanced skin-inflammation and decreased Treg frequency in lymph nodes. In RA patients, TNF blockade induced an increase in the frequency of TNFR2-expressing Tregs at 3 months of treatment vs. the baselineConclusionsTNFR2 signalling on Tregs may play a major role in controlling inflammation and can be activated both by TNF-α and anti-TNF treatment. Further studies to dissect TNFR2 dependent pathways on Tregs are warranted.ReferencesNie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med2013;19:322-8.Chen X, Wu X, Zhou Q, et al. TNFR2 is critical for the stabilisation of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory environment. J Immunol. 2013;190:1076-84.Nguyen DX, Ehrenstein MR. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J Exp Med2016;213:1241-53.

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Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF–TNF-RII binding in rheumatoid arthritis

Abstract: Nguyen and Ehrenstein reveal that anti-TNF antibodies paradoxically enhance membrane TNF–TNF-RII interactions to increase Foxp3 expression and confer upon T reg cells the ability to suppress Th17 cells in rheumatoid arthritis patients.

Cited by 157 publications

References 44 publications

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

Structural principles of tumor necrosis factor superfamily signaling

03.12 Tnfr2⁺regulatory t cells subpopulations are highly suppressive and are increased on anti-tnf treatment

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Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF–TNF-RII binding in rheumatoid arthritis

Abstract: Nguyen and Ehrenstein reveal that anti-TNF antibodies paradoxically enhance membrane TNF–TNF-RII interactions to increase Foxp3 expression and confer upon T reg cells the ability to suppress Th17 cells in rheumatoid arthritis patients.

Cited by 157 publications

References 44 publications

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

Structural principles of tumor necrosis factor superfamily signaling

03.12 Tnfr2+regulatory t cells subpopulations are highly suppressive and are increased on anti-tnf treatment

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03.12 Tnfr2⁺regulatory t cells subpopulations are highly suppressive and are increased on anti-tnf treatment