Abstract
Treatments that block tumour necrosis factor (TNF) have major beneficial effects in several autoimmune and rheumatic diseases, including rheumatoid arthritis. However, some patients do not respond to TNF inhibitor treatment and rare occurrences of paradoxical disease exacerbation have been reported. These limitations on the clinical efficacy of TNF inhibitors can be explained by the differences between TNF receptor 1 (TNFR1) and TNFR2 signalling and by the diverse effects of TNF on multiple immune cells, including FOXP3+ regulatory T cells. This basic knowledge sheds light on the consequences of TNF inhibitor therapies on regulatory T cells in treated patients and on the limitations of such treatment in the control of diseases with an autoimmune component. Accordingly, the next generation of drugs targeting TNF is likely to be based on agents that selectively block the binding of TNF to TNFR1 and on TNFR2 agonists. These approaches could improve the treatment of rheumatic diseases in the future.
Key points
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Tumour necrosis factor (TNF) is a major inflammatory cytokine that has deleterious effects in several rheumatic and autoimmune diseases as attested by the success of TNF inhibitor therapy.
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Some patients do not respond to TNF inhibitors and others develop paradoxical autoimmune exacerbations that can be explained by the immunoregulatory role of TNF.
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The pro-inflammatory and anti-inflammatory properties of TNF are largely segregated by the capacity of this cytokine to bind to TNF receptor 1 (TNFR1) and TNFR2, respectively.
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The anti-inflammatory effects of TNF are explained by its capacity to increase the proliferation, stability and suppressive function of FOXP3+ regulatory T cells via TNFR2 signalling.
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Antagonists of TNFR1 and agonists of TNFR2 constitute a new generation of drugs that might be more effective and have fewer adverse effects than classical TNF inhibitors.
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References
Feldmann, M. Translating molecular insights in autoimmunity into effective therapy. Annu. Rev. Immunol. 27, 1–27 (2009).
Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).
Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).
Silva-Fernandez, L. & Hyrich, K. Rheumatoid arthritis: when TNF inhibitors fail in RA — weighing up the options. Nat. Rev. Rheumatol. 10, 262–264 (2014).
Roda, G., Jharap, B., Neeraj, N. & Colombel, J. F. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin. Transl. Gastroenterol. 7, e135 (2016).
Esposito, M. et al. Survival rate of antitumour necrosis factor-alpha treatments for psoriasis in routine dermatological practice: a multicentre observational study. Br. J. Dermatol. 169, 666–672 (2013).
Ramos-Casals, M., Brito-Zeron, P., Soto, M. J., Cuadrado, M. J. & Khamashta, M. A. Autoimmune diseases induced by TNF-targeted therapies. Best Pract. Res. Clin. Rheumatol. 22, 847–861 (2008).
Ramos-Casals, M. et al. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun. Rev. 9, 188–193 (2010).
Brenner, D., Blaser, H. & Mak, T. W. Regulation of tumour necrosis factor signalling: live or let die. Nat. Rev. Immunol. 15, 362–374 (2015).
Conrad, C. et al. TNF blockade induces a dysregulated type 1 interferon response without autoimmunity in paradoxical psoriasis. Nat. Commun. 9, 25 (2018).
van Oosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996).
[No authors listed] TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 53, 457–465 (1999).
Aggarwal, B. B., Gupta, S. C. & Kim, J. H. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood 119, 651–665 (2012).
Kalliolias, G. D. & Ivashkiv, L. B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49–62 (2016).
Atretkhany, K. N., Gogoleva, V. S., Drutskaya, M. S. & Nedospasov, S. A. Distinct modes of TNF signaling through its two receptors in health and disease. J. Leukoc. Biol. 107, 893–905 (2020).
Salomon, B. L. et al. Tumor necrosis factor alpha and regulatory T cells in oncoimmunology. Front. Immunol. 9, 444 (2018).
Davignon, J. L. et al. Modulation of T-cell responses by anti-tumor necrosis factor treatments in rheumatoid arthritis: a review. Arthritis Res. Ther. 20, 229 (2018).
Horiuchi, T., Mitoma, H., Harashima, S., Tsukamoto, H. & Shimoda, T. Transmembrane TNF-α: structure, function and interaction with anti-TNF agents. Rheumatology 49, 1215–1228 (2010).
Lee, W. H., Seo, D., Lim, S. G. & Suk, K. Reverse signaling of tumor necrosis factor superfamily proteins in macrophages and microglia: superfamily portrait in the neuroimmune interface. Front. Immunol. 10, 262 (2019).
Qu, Y., Zhao, G. & Hui, L. Forward and reverse signaling mediated by transmembrane tumor necrosis factor-α and TNF receptor 2: potential roles in an immunosuppressive tumor microenvironment. Front. Immunol. 8, 1675 (2017).
Aggarwal, B. B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745–756 (2003).
Chen, X., Baumel, M., Mannel, D. N., Howard, O. M. & Oppenheim, J. J. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J. Immunol. 179, 154–161 (2007).
Ware, C. F. Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23, 787–819 (2005).
Yang, S., Wang, J., Brand, D. D. & Zheng, S. G. Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front. Immunol. 9, 784 (2018).
Faustman, D. & Davis, M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat. Rev. Drug Discov. 9, 482–493 (2010).
Gregory, A. P. et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508–511 (2012).
Park, H., Bourla, A. B., Kastner, D. L., Colbert, R. A. & Siegel, R. M. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat. Rev. Immunol. 12, 570–580 (2012).
Yang, S. et al. Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases. Cell Death Dis. 10, 27 (2019).
Rampart, M., De Smet, W., Fiers, W. & Herman, A. G. Inflammatory properties of recombinant tumor necrosis factor in rabbit skin in vivo. J. Exp. Med. 169, 2227–2232 (1989).
Venkatesh, D. et al. Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-β autocrine signaling to promote monocyte recruitment. Immunity 38, 1025–1037 (2013).
Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908–918 (2011).
Ding, X. et al. TNF receptor 1 mediates dendritic cell maturation and CD8 T cell response through two distinct mechanisms. J. Immunol. 187, 1184–1191 (2011).
Menges, M. et al. Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity. J. Exp. Med. 195, 15–21 (2002).
Noti, M., Corazza, N., Mueller, C., Berger, B. & Brunner, T. TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis. J. Exp. Med. 207, 1057–1066 (2010).
Wang, W. et al. Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell-mediated TNFα signaling. Sci. Transl. Med. 9, eaag3214 (2017).
Ghannam, S., Pene, J., Moquet-Torcy, G., Jorgensen, C. & Yssel, H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J. Immunol. 185, 302–312 (2010).
Sayegh, S. et al. Rheumatoid synovial fluids regulate the immunomodulatory potential of adipose-derived mesenchymal stem cells through a TNF/NF-κB-dependent mechanism. Front. Immunol. 10, 1482 (2019).
Raveney, B. J., Copland, D. A., Dick, A. D. & Nicholson, L. B. TNFR1-dependent regulation of myeloid cell function in experimental autoimmune uveoretinitis. J. Immunol. 183, 2321–2329 (2009).
Zhao, X. et al. TNF signaling drives myeloid-derived suppressor cell accumulation. J. Clin. Invest. 122, 4094–4104 (2012).
Chavez-Galan, L. et al. Transmembrane tumor necrosis factor controls myeloid-derived suppressor cell activity via TNF receptor 2 and protects from excessive inflammation during BCG-induced pleurisy. Front. Immunol. 8, 999 (2017).
Hu, X. et al. Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. J. Immunol. 192, 1320–1331 (2014).
Sade-Feldman, M. et al. Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38, 541–554 (2013).
Bachus, H. et al. Impaired tumor-necrosis-factor-α-driven dendritic cell activation limits lipopolysaccharide-induced protection from allergic inflammation in infants. Immunity 50, 225–240.e4 (2019).
Alzabin, S. et al. Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. Ann. Rheum. Dis. 71, 1741–1748 (2012).
Mayordomo, A. C. et al. IL-12/23p40 overproduction by dendritic cells leads to an increased Th1 and Th17 polarization in a model of Yersinia enterocolitica-induced reactive arthritis in TNFRp55–/– mice. PLoS ONE 13, e0193573 (2018).
Notley, C. A. et al. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J. Exp. Med. 205, 2491–2497 (2008).
Park, S. H., Park-Min, K. H., Chen, J., Hu, X. & Ivashkiv, L. B. Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages. Nat. Immunol. 12, 607–615 (2011).
Zakharova, M. & Ziegler, H. K. Paradoxical anti-inflammatory actions of TNF-α: inhibition of IL-12 and IL-23 via TNF receptor 1 in macrophages and dendritic cells. J. Immunol. 175, 5024–5033 (2005).
Kusnadi, A. et al. The cytokine TNF promotes transcription factor SREBP activity and binding to inflammatory genes to activate macrophages and limit tissue repair. Immunity 51, 241–257.e9 (2019).
Park, S. H. et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat. Immunol. 18, 1104–1116 (2017).
Tartaglia, L. A. et al. Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. J. Immunol. 151, 4637–4641 (1993).
Kim, E. Y. & Teh, H. S. Critical role of TNF receptor type-2 (p75) as a costimulator for IL-2 induction and T cell survival: a functional link to CD28. J. Immunol. 173, 4500–4509 (2004).
Kim, E. Y., Priatel, J. J., Teh, S. J. & Teh, H. S. TNF receptor type 2 (p75) functions as a costimulator for antigen-driven T cell responses in vivo. J. Immunol. 176, 1026–1035 (2006).
Calzascia, T. et al. TNF-α is critical for antitumor but not antiviral T cell immunity in mice. J. Clin. Invest. 117, 3833–3845 (2007).
Chen, X. et al. TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis. Sci. Rep. 6, 32834 (2016).
Soloviova, K., Puliaiev, M., Haas, M. & Via, C. S. In vivo maturation of allo-specific CD8 CTL and prevention of lupus-like graft-versus-host disease is critically dependent on T cell signaling through the TNF p75 receptor but not the TNF p55 receptor. J. Immunol. 190, 4562–4572 (2013).
de Kivit, S. et al. Stable human regulatory T cells switch to glycolysis following TNF receptor 2 costimulation. Nat. Metab. 2, 1046–1061 (2020).
Schioppa, T. et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc. Natl Acad. Sci. USA 108, 10662–10667 (2011).
Cope, A. P. et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J. Exp. Med. 185, 1573–1584 (1997).
Aspalter, R. M., Wolf, H. M. & Eibl, M. M. Chronic TNF-α exposure impairs TCR-signaling via TNF-RII but not TNF-RI. Cell Immunol. 237, 55–67 (2005).
Beyer, M. et al. Tumor-necrosis factor impairs CD4+ T cell-mediated immunological control in chronic viral infection. Nat. Immunol. 17, 593–603 (2016).
Qin, H. Y., Chaturvedi, P. & Singh, B. In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-γ/TNF-α. Int. Immunol. 16, 1723–1732 (2004).
Naude, P. J., den Boer, J. A., Luiten, P. G. & Eisel, U. L. Tumor necrosis factor receptor cross-talk. FEBS J. 278, 888–898 (2011).
Lin, R. H., Hwang, Y. W., Yang, B. C. & Lin, C. S. TNF receptor-2-triggered apoptosis is associated with the down-regulation of Bcl-xL on activated T cells and can be prevented by CD28 costimulation. J. Immunol. 158, 598–603 (1997).
Ban, L. et al. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc. Natl Acad. Sci. USA 105, 13644–13649 (2008).
Bhattacharyya, S. et al. Tumor-induced oxidative stress perturbs nuclear factor-κB activity-augmenting tumor necrosis factor-α-mediated T-cell death: protection by curcumin. Cancer Res. 67, 362–370 (2007).
Kim, E. Y., Teh, S. J., Yang, J., Chow, M. T. & Teh, H. S. TNFR2-deficient memory CD8 T cells provide superior protection against tumor cell growth. J. Immunol. 183, 6051–6057 (2009).
Luckey, U. et al. T cell killing by tolerogenic dendritic cells protects mice from allergy. J. Clin. Invest. 121, 3860–3871 (2011).
Miller, P. G., Bonn, M. B. & McKarns, S. C. Transmembrane TNF-TNFR2 impairs Th17 differentiation by promoting Il2 expression. J. Immunol. 195, 2633–2647 (2015).
Urbano, P. C. M. et al. TNF-α-induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-α blockade-driven IL-17A expression. J. Allergy Clin. Immunol. 142, 517–529 (2018).
Urbano, P. C. M. et al. TNFα-signaling modulates the kinase activity of human effector Treg and regulates IL-17A expression. Front. Immunol. 10, 3047 (2019).
Elicabe, R. J. et al. Lack of TNFR p55 results in heightened expression of IFN-γ and IL-17 during the development of reactive arthritis. J. Immunol. 185, 4485–4495 (2010).
Ma, H. L. et al. Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum. 62, 430–440 (2010).
Hull, D. N. et al. Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis. Clin. Exp. Immunol. 181, 401–406 (2015).
Talotta, R. et al. Paradoxical expansion of Th1 and Th17 lymphocytes in rheumatoid arthritis following infliximab treatment: a possible explanation for a lack of clinical response. J. Clin. Immunol. 35, 550–557 (2015).
Kruglov, A. A., Lampropoulou, V., Fillatreau, S. & Nedospasov, S. A. Pathogenic and protective functions of TNF in neuroinflammation are defined by its expression in T lymphocytes and myeloid cells. J. Immunol. 187, 5660–5670 (2011).
Kruglov, A. et al. Contrasting contributions of TNF from distinct cellular sources in arthritis. Ann. Rheum. Dis. 79, 1453–1459 (2020).
Wolf, Y. et al. Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation. J. Exp. Med. 214, 905–917 (2017).
Mukai, Y. et al. Solution of the structure of the TNF-TNFR2 complex. Sci. Signal. 3, ra83 (2010).
Chan, F. K. The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function. Ann. Rheum. Dis. 59 (Suppl. 1), i50–i53 (2000).
Croft, M. & Siegel, R. M. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat. Rev. Rheumatol. 13, 217–233 (2017).
Van Hauwermeiren, F., Vandenbroucke, R. E. & Libert, C. Treatment of TNF mediated diseases by selective inhibition of soluble TNF or TNFR1. Cytokine Growth Factor. Rev. 22, 311–319 (2011).
Alexopoulou, L. et al. Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity. Eur. J. Immunol. 36, 2768–2780 (2006).
Nguyen, D. X. & Ehrenstein, M. R. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J. Exp. Med. 213, 1241–1253 (2016).
Grell, M. et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83, 793–802 (1995).
Medler, J. & Wajant, H. Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target. Expert Opin. Ther. Targets 23, 295–307 (2019).
So, T. & Croft, M. Regulation of PI-3-kinase and Akt signaling in T lymphocytes and other cells by TNFR family molecules. Front. Immunol. 4, 139 (2013).
Wajant, H. & Beilhack, A. Targeting regulatory T cells by addressing tumor necrosis factor and its receptors in allogeneic hematopoietic cell transplantation and cancer. Front. Immunol. 10, 2040 (2019).
Twu, Y. C., Gold, M. R. & Teh, H. S. TNFR1 delivers pro-survival signals that are required for limiting TNFR2-dependent activation-induced cell death (AICD) in CD8+ T cells. Eur. J. Immunol. 41, 335–344 (2011).
Catrina, A. C. et al. Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. Arthritis Rheum. 52, 61–72 (2005).
Mitoma, H. et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells. Arthritis Rheum. 58, 1248–1257 (2008).
Tada, Y. et al. Collagen-induced arthritis in TNF receptor-1-deficient mice: TNF receptor-2 can modulate arthritis in the absence of TNF receptor-1. Clin. Immunol. 99, 325–333 (2001).
Lee, L. F. et al. The role of TNF-α in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation. Proc. Natl Acad. Sci. USA 102, 15995–16000 (2005).
McDevitt, H., Munson, S., Ettinger, R. & Wu, A. Multiple roles for tumor necrosis factor-α and lymphotoxin α/β in immunity and autoimmunity. Arthritis Res. 4 (Suppl. 3), S141–S152 (2002).
Green, E. A. & Flavell, R. A. The temporal importance of TNFα expression in the development of diabetes. Immunity 12, 459–469 (2000).
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
Buckner, J. H. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat. Rev. Immunol. 10, 849–859 (2010).
Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J. Exp. Med. 200, 277–285 (2004).
Dige, A. et al. Adalimumab treatment in Crohn’s disease does not induce early changes in regulatory T cells. Scand. J. Gastroenterol. 46, 1206–1214 (2011).
Li, Z. et al. Restoration of Foxp3+ regulatory T-cell subsets and Foxp3– type 1 regulatory-like T cells in inflammatory bowel diseases during anti-tumor necrosis factor therapy. Inflamm. Bowel Dis. 21, 2418–2428 (2015).
Bluestone, J. A. & Tang, Q. Treg cells — the next frontier of cell therapy. Science 362, 154–155 (2018).
Zemmour, D. et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat. Immunol. 19, 291–301 (2018).
Lubrano di Ricco, M. et al. Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-κB. Eur. J. Immunol. 50, 972–985 (2020).
Vasanthakumar, A. et al. The TNF receptor superfamily-NF-κB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues. Cell Rep. 20, 2906–2920 (2017).
Chen, X. et al. Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FoxP3+ regulatory T cells in human peripheral blood. Eur. J. Immunol. 40, 1099–1106 (2010).
Chen, X. et al. Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J. Immunol. 180, 6467–6471 (2008).
Hamano, R., Huang, J., Yoshimura, T., Oppenheim, J. J. & Chen, X. TNF optimally activates regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. Eur. J. Immunol. 41, 2010–2020 (2011).
Grinberg-Bleyer, Y. et al. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J. Clin. Invest. 120, 4558–4568 (2010).
Baeyens, A. et al. Effector T cells boost regulatory T cell expansion by IL-2, TNF, OX40, and plasmacytoid dendritic cells depending on the immune context. J. Immunol. 194, 999–1010 (2015).
Zhou, Q., Hu, Y., Howard, O. M., Oppenheim, J. J. & Chen, X. In vitro generated Th17 cells support the expansion and phenotypic stability of CD4+Foxp3+ regulatory T cells in vivo. Cytokine 65, 56–64 (2014).
Okubo, Y., Mera, T., Wang, L. & Faustman, D. L. Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci. Rep. 3, 3153 (2013).
Urbano, P. C. M., Koenen, H., Joosten, I. & He, X. An autocrine TNFα-tumor necrosis factor receptor 2 loop promotes epigenetic effects inducing human Treg stability in vitro. Front. Immunol. 9, 573 (2018).
Chen, X. et al. TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J. Immunol. 190, 1076–1084 (2013).
Housley, W. J. et al. Natural but not inducible regulatory T cells require TNF-α signaling for in vivo function. J. Immunol. 186, 6779–6787 (2011).
Santinon, F. et al. Involvement of tumor necrosis factor receptor type II in FoxP3 stability and as a marker of Treg cells specifically expanded by anti-tumor necrosis factor treatments in rheumatoid arthritis. Arthritis Rheumatol. 72, 576–587 (2020).
Ban, L. et al. Strategic internal covalent cross-linking of TNF produces a stable TNF trimer with improved TNFR2 signaling. Mol. Cell Ther. 3, 7 (2015).
Chopra, M. et al. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. J. Exp. Med. 213, 1881–1900 (2016).
He, X. et al. A TNFR2-agonist facilitates high purity expansion of human low purity Treg cells. PLoS ONE 11, e0156311 (2016).
Fischer, R. et al. Selective activation of tumor necrosis factor receptor II induces antiinflammatory responses and alleviates experimental arthritis. Arthritis Rheumatol. 70, 722–735 (2018).
Joedicke, J. J. et al. Activated CD8+ T cells induce expansion of Vβ5+ regulatory T cells via TNFR2 signaling. J. Immunol. 193, 2952–2960 (2014).
Lamontain, V. et al. Stimulation of TNF receptor type 2 expands regulatory T cells and ameliorates established collagen-induced arthritis in mice. Cell Mol. Immunol. 16, 65–74 (2019).
Nagar, M. et al. TNF activates a NF-κB-regulated cellular program in human CD45RA– regulatory T cells that modulates their suppressive function. J. Immunol. 184, 3570–3581 (2010).
Wang, J. et al. TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-κB pathway. Sci. Rep. 8, 12079 (2018).
Bittner, S. & Ehrenschwender, M. Multifaceted death receptor 3 signaling-promoting survival and triggering death. FEBS Lett. 591, 2543–2555 (2017).
He, T. et al. The p38 MAPK inhibitor SB203580 abrogates tumor necrosis factor-induced proliferative expansion of mouse CD4+Foxp3+ regulatory T cells. Front. Immunol. 9, 1556 (2018).
Nie, H. et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat. Med. 19, 322–328 (2013).
Stoop, J. N. et al. Tumor necrosis factor α inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response. Hepatology 46, 699–705 (2007).
Valencia, X. et al. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108, 253–261 (2006).
Zanin-Zhorov, A. et al. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328, 372–376 (2010).
Pierini, A. et al. TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128, 866–871 (2016).
Leclerc, M. et al. Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells. Blood 128, 1651–1659 (2016).
Ronin, E. et al. Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2-expressing Treg cells. Proc. Natl Acad. Sci. USA 118, e2014043118 (2021).
Zaragoza, B. et al. Suppressive activity of human regulatory T cells is maintained in the presence of TNF. Nat. Med. 22, 16–17 (2016).
Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).
Chen, X. et al. Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3– conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J. Immunol. 185, 174–182 (2010).
Yamaguchi, T., Wing, J. B. & Sakaguchi, S. Two modes of immune suppression by Foxp3+ regulatory T cells under inflammatory or non-inflammatory conditions. Semin. Immunol. 23, 424–430 (2011).
Chaudhry, A. & Rudensky, A. Y. Control of inflammation by integration of environmental cues by regulatory T cells. J. Clin. Invest. 123, 939–944 (2013).
Williams, L. M. & Rudensky, A. Y. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat. Immunol. 8, 277–284 (2007).
Chinen, T. et al. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17, 1322–1333 (2016).
Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).
Gao, Y. et al. Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc. Natl Acad. Sci. USA 112, E3246–E3254 (2015).
Xie, M. et al. NF-κB-driven miR-34a impairs Treg/Th17 balance via targeting Foxp3. J. Autoimmun. 102, 96–113 (2019).
Molinero, L. L., Miller, M. L., Evaristo, C. & Alegre, M. L. High TCR stimuli prevent induced regulatory T cell differentiation in a NF-κB-dependent manner. J. Immunol. 186, 4609–4617 (2011).
Zhang, Q. et al. TNF-α impairs differentiation and function of TGF-β-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway. J. Mol. Cell Biol. 5, 85–98 (2013).
Mahmud, S. A. et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15, 473–481 (2014).
Nadkarni, S., Mauri, C. & Ehrenstein, M. R. Anti-TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β. J. Exp. Med. 204, 33–39 (2007).
So, T. & Croft, M. Cutting edge: OX40 inhibits TGF-β- and antigen-driven conversion of naive CD4 T cells into CD25+Foxp3+ T cells. J. Immunol. 179, 1427–1430 (2007).
Madireddi, S. et al. SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ. PLoS ONE 7, e42459 (2012).
Khan, S. Q. et al. Cloning, expression, and functional characterization of TL1A-Ig. J. Immunol. 190, 1540–1550 (2013).
Lina, C., Conghua, W., Nan, L. & Ping, Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J. Clin. Immunol. 31, 596–605 (2011).
Toubi, E. et al. Increased spontaneous apoptosis of CD4+CD25+ T cells in patients with active rheumatoid arthritis is reduced by infliximab. Ann. NY Acad. Sci. 1051, 506–514 (2005).
Cao, D., van Vollenhoven, R., Klareskog, L., Trollmo, C. & Malmstrom, V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res. Ther. 6, R335–R346 (2004).
Dombrecht, E. J. et al. Influence of anti-tumor necrosis factor therapy (adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin. Exp. Rheumatol. 24, 31–37 (2006).
McGovern, J. L. et al. Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum. 64, 3129–3138 (2012).
van Amelsfort, J. M., Jacobs, K. M., Bijlsma, J. W., Lafeber, F. P. & Taams, L. S. CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 50, 2775–2785 (2004).
Cao, D. et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur. J. Immunol. 33, 215–223 (2003).
Herrath, J. et al. The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function. Eur. J. Immunol. 41, 2279–2290 (2011).
Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).
Chen, Z. et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272–285 (2013).
van Loosdregt, J. et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39, 259–271 (2013).
Huang, Z. et al. Anti-TNF-α therapy improves Treg and suppresses Teff in patients with rheumatoid arthritis. Cell Immunol. 279, 25–29 (2012).
Blache, C. et al. Number and phenotype of rheumatoid arthritis patients’ CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept. Rheumatology 50, 1814–1822 (2011).
Hvas, C. L. et al. Discrete changes in circulating regulatory T cells during infliximab treatment of Crohn’s disease. Autoimmunity 43, 325–333 (2010).
Boschetti, G. et al. Therapy with anti-TNFα antibody enhances number and function of Foxp3+ regulatory T cells in inflammatory bowel diseases. Inflamm. Bowel Dis. 17, 160–170 (2011).
Kato, K. et al. Infliximab therapy impacts the peripheral immune system of immunomodulator and corticosteroid naive patients with Crohn’s disease. Gut Liver 5, 37–45 (2011).
Li, Z. et al. Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. Inflamm. Bowel Dis. 16, 1299–1310 (2010).
Ricciardelli, I., Lindley, K. J., Londei, M. & Quaratino, S. Anti tumour necrosis-α therapy increases the number of FOXP3 regulatory T cells in children affected by Crohn’s disease. Immunology 125, 178–183 (2008).
Veltkamp, C. et al. Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFα treatment. Gut 60, 1345–1353 (2011).
Calleja, S. et al. Adalimumab specifically induces CD3+ CD4+ CD25high Foxp3+ CD127– T-regulatory cells and decreases vascular endothelial growth factor plasma levels in refractory immuno-mediated uveitis: a non-randomized pilot intervention study. Eye 26, 468–477 (2012).
Sugita, S., Yamada, Y., Kaneko, S., Horie, S. & Mochizuki, M. Induction of regulatory T cells by infliximab in Behcet’s disease. Invest. Ophthalmol. Vis. Sci. 52, 476–484 (2011).
Xueyi, L. et al. Levels of circulating Th17 cells and regulatory T cells in ankylosing spondylitis patients with an inadequate response to anti-TNF-α therapy. J. Clin. Immunol. 33, 151–161 (2013).
Wehrens, E. J. et al. Anti-tumor necrosis factor alpha targets protein kinase B/c-Akt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis. Arthritis Rheum. 65, 3279–3284 (2013).
Verwoerd, A. et al. Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis. Clin. Exp. Immunol. 185, 263–270 (2016).
Nguyen, D. X. et al. Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis. J. Allergy Clin. Immunol. 142, 978–980.e9 (2018).
Chen, X., Oppenheim, J. J., Winkler-Pickett, R. T., Ortaldo, J. R. & Howard, O. M. Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3+CD4+CD25+ T regulatory cells in vivo and enhances their capacity to suppress EAE. Eur. J. Immunol. 36, 2139–2149 (2006).
Kim, D. et al. Anti-inflammatory roles of glucocorticoids are mediated by Foxp3+ regulatory T cells via a miR-342-dependent mechanism. Immunity 53, 581–596 (2020).
Byng-Maddick, R. & Ehrenstein, M. R. The impact of biological therapy on regulatory T cells in rheumatoid arthritis. Rheumatology 54, 768–775 (2015).
Di Sabatino, A. et al. Peripheral regulatory T cells and serum transforming growth factor-β: relationship with clinical response to infliximab in Crohn’s disease. Inflamm. Bowel Dis. 16, 1891–1897 (2010).
Zou, H., Li, R., Hu, H., Hu, Y. & Chen, X. Modulation of regulatory T cell activity by TNF receptor type II-targeting pharmacological agents. Front. Immunol. 9, 594 (2018).
Fischer, R., Kontermann, R. E. & Pfizenmaier, K. Selective targeting of TNF receptors as a novel therapeutic approach. Front. Cell Dev. Biol. 8, 401 (2020).
Mukai, Y. et al. Structure-function relationship of tumor necrosis factor (TNF) and its receptor interaction based on 3D structural analysis of a fully active TNFR1-selective TNF mutant. J. Mol. Biol. 385, 1221–1229 (2009).
Ando, D. et al. Creation of mouse TNFR2-selective agonistic TNF mutants using a phage display technique. Biochem. Biophys. Rep. 7, 309–315 (2016).
Van Ostade, X., Vandenabeele, P., Tavernier, J. & Fiers, W. Human tumor necrosis factor mutants with preferential binding to and activity on either the R55 or R75 receptor. Eur. J. Biochem. 220, 771–779 (1994).
McCann, F. E. et al. Selective tumor necrosis factor receptor I blockade is antiinflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis. Arthritis Rheumatol. 66, 2728–2738 (2014).
Williams, S. K. et al. Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis. Sci. Rep. 8, 13628 (2018).
Steeland, S. et al. TNFR1 inhibition with a nanobody protects against EAE development in mice. Sci. Rep. 7, 13646 (2017).
Williams, S. K. et al. Antibody-mediated inhibition of TNFR1 attenuates disease in a mouse model of multiple sclerosis. PLoS ONE 9, e90117 (2014).
Zalevsky, J. et al. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J. Immunol. 179, 1872–1883 (2007).
Shibata, H. et al. The treatment of established murine collagen-induced arthritis with a TNFR1-selective antagonistic mutant TNF. Biomaterials 30, 6638–6647 (2009).
Brambilla, R. et al. Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain 134, 2736–2754 (2011).
Nomura, T. et al. Therapeutic effect of PEGylated TNFR1-selective antagonistic mutant TNF in experimental autoimmune encephalomyelitis mice. J. Control. Rel. 149, 8–14 (2011).
Taoufik, E. et al. Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-κB. Brain 134, 2722–2735 (2011).
Maier, O., Fischer, R., Agresti, C. & Pfizenmaier, K. TNF receptor 2 protects oligodendrocyte progenitor cells against oxidative stress. Biochem. Biophys. Res. Commun. 440, 336–341 (2013).
Rauert, H. et al. Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). J. Biol. Chem. 285, 7394–7404 (2009).
Dong, Y. et al. Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration. Proc. Natl Acad. Sci. USA 113, 12304–12309 (2016).
Fischer, R. et al. TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes. Proc. Natl Acad. Sci. USA 116, 17045–17050 (2019).
Klatzmann, D. & Abbas, A. K. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat. Rev. Immunol. 15, 283–294 (2015).
Grinberg-Bleyer, Y. et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878 (2010).
Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).
Mori, L., Iselin, S., De Libero, G. & Lesslauer, W. Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J. Immunol. 157, 3178–3182 (1996).
Tseng, W. Y. et al. TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells. Proc. Natl Acad. Sci. USA 116, 21666–21672 (2019).
Bluml, S. et al. Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis. Arthritis Rheum. 62, 1608–1619 (2010).
Eugster, H. P. et al. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur. J. Immunol. 29, 626–632 (1999).
Suvannavejh, G. C. et al. Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG(35-55)-induced experimental autoimmune encephalomyelitis. Cell Immunol. 205, 24–33 (2000).
Kassiotis, G. & Kollias, G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J. Exp. Med. 193, 427–434 (2001).
Miller, P. G., Bonn, M. B., Franklin, C. L., Ericsson, A. C. & McKarns, S. C. TNFR2 deficiency acts in concert with gut microbiota to precipitate spontaneous sex-biased central nervous system demyelinating autoimmune disease. J. Immunol. 195, 4668–4684 (2015).
Wang, Y. L. et al. Targeting pre-ligand assembly domain of TNFR1 ameliorates autoimmune diseases — an unrevealed role in downregulation of Th17 cells. J. Autoimmun. 37, 160–170 (2011).
Fischer, R. et al. Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis. Brain Behav. Immun. 81, 247–259 (2019).
Acknowledgements
The author thanks current and past members of his laboratory for their hard work and fruitful and passionate exchanges on the effects of TNF on Treg cells. His research work is supported by Agence Nationale de la Recherche (grants ANR-15-CE15-0015-03 and ANR-17-CE15-0030-01) and Fondation pour la Recherche Médicale (équipe FRM).
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B.L.S. declares that he received consultancy fees from HiFiBio Therapeutics regarding the applications of TNFR2 agonists and antagonists in cancer and autoimmunity.
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Nature Reviews Rheumatology thanks R. Williams, M. Ehrenstein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Salomon, B.L. Insights into the biology and therapeutic implications of TNF and regulatory T cells. Nat Rev Rheumatol 17, 487–504 (2021). https://doi.org/10.1038/s41584-021-00639-6
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DOI: https://doi.org/10.1038/s41584-021-00639-6
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