Abstract
The puzzling biphasic or dual roles of tumor necrosis factor α (TNF) in the inflammatory and immune responses are likely to be mediated by distinct signaling pathways transduced by one of its two receptors, e.g., TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). Unlike TNFR1 that is ubiquitously expressed on almost all types of cells, the expression of TNFR2 is rather restricted to certain types of cells, such as T lymphocytes. There is now compelling evidence that TNFR2 is preferentially expressed by CD4+Foxp3+ regulatory T cells (Tregs), and TNFR2 plays a decisive role in the activation, expansion, in vivo function, and phenotypical stability of Tregs. In this chapter, the current understanding of the molecular basis and signaling pathway of TNF–TNFRs signal is introduced. Latest studies that have further supported and substantiated the pivotal role of TNF–TNFR2 interaction in Tregs biology and its molecular basis are discussed. The research progress regarding TNFR2-targeting treatment for autoimmune diseases and cancer is analyzed. Future study should focus on the further understanding of molecular mechanism underlying Treg-stimulatory effect of TNFR2 signal, as well as on the translation of research findings into therapeutic benefits of human patients with autoimmune diseases, allergy, allograft rejection, and cancer.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Aggarwal BB (1991) Structure of tumor necrosis factor and its receptor. Biotherapy 3(2):113–120. https://doi.org/10.1007/BF02172083
Al-Hatamleh MAI, E A R ENS, Boer JC, Ferji K, Six J-L, Chen X et al (2019a) Synergistic effects of nanomedicine targeting TNFR2 and DNA demethylation inhibitor-an opportunity for cancer treatment. Cell 9(1):33. https://doi.org/10.3390/cells9010033
Al-Hatamleh MAI, Ahmad S, Boer JC, Lim J, Chen X, Plebanski M et al (2019b) A perspective review on the role of nanomedicine in the modulation of TNF-TNFR2 axis in breast cancer immunotherapy. J Oncol 2019:6313242. https://doi.org/10.1155/2019/6313242
Annunziato F, Cosmi L, Liotta F, Lazzeri E, Manetti R, Vanini V et al (2002) Phenotype, localization, and mechanism of suppression of CD4+CD25+ human thymocytes. J Exp Med 196(3):379–387. https://doi.org/10.1084/jem.20020110
Bach E, Nielsen RR, Vendelbo MH, Møller AB, Jessen N, Buhl M et al (2013) Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo-controlled, bilaterally infused human leg: increased insulin sensitivity, increased net protein breakdown, and increased IL-6 release. Diabetes 62(12):4023–4029. https://doi.org/10.2337/db13-0138
Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL (2008) Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci U S A 105(36):13644–13649. https://doi.org/10.1073/pnas.0803429105
Battegay EJ, Raines EW, Colbert T, Ross R (1995) TNF-alpha stimulation of fibroblast proliferation. Dependence on platelet-derived growth factor (PDGF) secretion and alteration of PDGF receptor expression. J Immunol 154(11):6040–6047
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21. https://doi.org/10.1038/83713
Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM (2002) Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46(12):3151–3158. https://doi.org/10.1002/art.10679
Cabal-Hierro L, Lazo PS (2012) Signal transduction by tumor necrosis factor receptors. Cell Signal 24(6):1297–1305. https://doi.org/10.1016/j.cellsig.2012.02.006
Cawthorn WP, Sethi JK (2008) TNF-alpha and adipocyte biology. FEBS Lett 582(1):117–131. https://doi.org/10.1016/j.febslet.2007.11.051
Chen X, Oppenheim JJ (2010) TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Curr Dir Autoimmun 11:119–134. https://doi.org/10.1159/000289201
Chen X, Oppenheim JJ (2011a) Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity. FEBS Lett 585(23):3611–3618. https://doi.org/10.1016/j.febslet.2011.04.025
Chen X, Oppenheim JJ (2011b) The phenotypic and functional consequences of tumour necrosis factor receptor type 2 expression on CD4(+) FoxP3(+) regulatory T cells. Immunology 133(4):426–433. https://doi.org/10.1111/j.1365-2567.2011.03460.x
Chen X, Oppenheim JJ (2011c) Resolving the identity myth: key markers of functional CD4+FoxP3+ regulatory T cells. Int Immunopharmacol 11(10):1489–1496. https://doi.org/10.1016/j.intimp.2011.05.018
Chen X, Oppenheim JJ (2014) Th17 cells and Tregs: unlikely allies. J Leukoc Biol 95(5):723–731. https://doi.org/10.1189/jlb.1213633
Chen X, Oppenheim JJ (2016) Therapy: paradoxical effects of targeting TNF signalling in the treatment of autoimmunity. Nat Rev Rheumatol 12(11):625–626. https://doi.org/10.1038/nrrheum.2016.145
Chen X, Oppenheim JJ (2017) Targeting TNFR2, an immune checkpoint stimulator and oncoprotein, is a promising treatment for cancer. Sci Signal 10(462):1–3. https://doi.org/10.1126/scisignal.aal2328
Chen X, Plebanski M (2019) The role of TNF-TNFR2 signal in immunosuppressive cells and its therapeutic implications. Front Immunol 10:2126. https://doi.org/10.3389/fimmu.2019.02126
Chen X, Bäumel M, Männel DN, Howard OZ, Oppenheim JJ (2007) Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+ CD25+ T regulatory cells. J Immunol 179(1):154–161. https://doi.org/10.4049/jimmunol.179.1.154
Chen X, Subleski JJ, Kopf H, Howard OMZ, Männel DN, Oppenheim JJ (2008) Cutting edge: expression of TNFR2 defines a unique subset of mouse CD4+CD25+ T regulatory cells with maximal suppressive functions: applicability to tumor infiltrating T regulatory cells. J Immunol 180(10):6467–6471. https://doi.org/10.4049/jimmunol.180.10.6467
Chen X, Xun K, Chen L, Wang Y (2009) TNF-α, a potent lipid metabolism regulator. Cell Biochem Funct 27(7):407–416. https://doi.org/10.1002/cbf.1596
Chen X, Subleski JJ, Hamano R, Howard OMZ, Wiltrout RH, Oppenheim JJ (2010a) Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood. Eur J Immunol 40(4):1099–1106. https://doi.org/10.1002/eji.200940022
Chen X, Hamano R, Subleski JJ, Hurwitz AA, Howard OM, Oppenheim JJ (2010b) Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3- conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol 185(1):174–182. https://doi.org/10.4049/jimmunol.0903548
Chen X, Wu X, Zhou Q, Howard OM, Netea MG, Oppenheim JJ (2013) TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J Immunol 190(3):1076–1084. https://doi.org/10.4049/jimmunol.1202659
Chen X, Willette-Brown J, Wu X, Hu Y, Howard OM, Oppenheim JJ (2015) IKKα is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells. FASEB J 29(2):443–454. https://doi.org/10.1096/fj.14-259564.
Chen X, Nie Y, **ao H, Bian Z, Scarzello AJ, Song NY et al (2016) TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis. Sci Rep 6:32834. https://doi.org/10.1038/srep32834
Cho Y, Challa S, Moquin D, Genga R, Ray TD, Guildford M et al (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137(6):1112–1123. https://doi.org/10.1016/j.cell.2009.05.037
Chopra M, Biehl M, Steinfatt T, Brandl A, Kums J, Amich J et al (2016) Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. J Exp Med 213(9):1881–1900. https://doi.org/10.1084/jem.20151563
Cohen JL, Wood KJ (2018) TNFR2: the new Treg switch? OncoImmunology 7(1):e1373236. https://doi.org/10.1080/2162402X.2017.1373236
Dong Y, Fischer R, Naude PJ, Maier O, Nyakas C, Duffey M et al (2016) Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration. Proc Natl Acad Sci U S A 113(43):12304–12309. https://doi.org/10.1073/pnas.1605195113
Drabarek B, Dymkowska D, Szczepanowska J, Zablocki K (2012) TNFα affects energy metabolism and stimulates biogenesis of mitochondria in EA.hy926 endothelial cells. Int J Biochem Cell Biol 44(9):1390–1397. https://doi.org/10.1016/j.biocel.2012.05.022
Faustman DL (2018) TNF, TNF inducers, and TNFR2 agonists: a new path to type 1 diabetes treatment. Diabetes Metab Res Rev 34(1):e2941. https://doi.org/10.1002/dmrr.2941
Faustman D, Davis M (2010) TNF receptor 2 pathway: drug target for autoimmune diseases. Nat Rev Drug Discov 9(6):482–493. https://doi.org/10.1038/nrd3030
Faustman D, Eisenbarth G, Daley J, Breitmeyer J (1989) Abnormal T-lymphocyte subsets in type I diabetes. Diabetes 38(11):1462–1468. https://doi.org/10.2337/diab.38.11.1462
Fischer R, Maier O, Siegemund M, Wajant H, Scheurich P, Pfizenmaier K (2011) A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death. PLoS One 6(11):e27621. https://doi.org/10.1371/journal.pone.0027621
Fischer R, Wajant H, Kontermann R, Pfizenmaier K, Maier O (2014) Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor. Glia 62(2):272–283. https://doi.org/10.1002/glia.22605
Fischer R, Marsal J, Guttà C, Eisler SA, Peters N, Bethea JR et al (2017) Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2. Sci Rep 7(1):6607. https://doi.org/10.1038/s41598-017-06993-4
Fischer R, Sendetski M, Del Rivero T, Martinez GF, Bracchi-Ricard V, Swanson KA et al (2019a) TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes. Proc Natl Acad Sci U S A 116(34):17045–17050. https://doi.org/10.1073/pnas.1902091116
Fischer R, Padutsch T, Bracchi-Ricard V, Murphy KL, Martinez GF, Delguercio N et al (2019b) 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. https://doi.org/10.1016/j.bbi.2019.06.021
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336. https://doi.org/10.1038/ni904
Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF et al (2006) SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production. Nat Cell Biol 8(8):843–848. https://doi.org/10.1038/ncb1440
Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA et al (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445(7129):771–775. https://doi.org/10.1038/nature05543
Gehr G, Gentz R, Brockhaus M, Loetscher H, Lesslauer W (1992) Both tumor necrosis factor receptor types mediate proliferative signals in human mononuclear cell activation. J Immunol 149(3):911–917
Govindaraj C, Scalzo-Inguanti K, Madondo M, Hallo J, Flanagan K, Quinn M et al (2013) Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin Immunol 149(1):97–110. https://doi.org/10.1016/j.clim.2013.07.003
Govindaraj C, Tan P, Walker P, Wei A, Spencer A, Plebanski M (2014a) Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients. Clin Cancer Res 20(3):724–735. https://doi.org/10.1158/1078-0432.CCR-13-1576
Govindaraj C, Madondo M, Kong YY, Tan P, Wei A, Plebanski M (2014b) Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients. Am J Hematol 89(8):795–802. https://doi.org/10.1002/ajh.23746
Gregory AP, Dendrou CA, Attfield KE, Haghikia A, **fara DK, Butter F et al (2012) TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488(7412):508–511. https://doi.org/10.1038/nature11307
Grell M, Douni E, Wajant H, Löhden M, Clauss M, Maxeiner B et al (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83(5):793–802. https://doi.org/10.1016/0092-8674(95)90192-2
Grell M, Wajant H, Zimmermann G, Scheurich P (1998) The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci U S A 95(2):570–575. https://doi.org/10.1073/pnas.95.2.570
Grinberg-Bleyer Y, Saadoun D, Baeyens A, Billiard F, Goldstein JD, Gregoire S et al (2010) Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J Clin Invest 120(12):4558–4568. https://doi.org/10.1172/jci42945
Gu J, Lu L, Chen M, Xu L, Lan Q, Li Q et al (2014) TGF-beta-induced CD4+Foxp3+ T cells attenuate acute graft-versus-host disease by suppressing expansion and killing of effector CD8+ cells. J Immunol 193(7):3388–3397. https://doi.org/10.4049/jimmunol.1400207
Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E et al (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36(5):831–844. https://doi.org/10.1016/j.molcel.2009.10.013
Hamano R, Huang J, Yoshimura T, Oppenheim JJ, Chen X (2011) TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. Eur J Immunol 41(7):2010–2020. https://doi.org/10.1002/eji.201041205
Hamano R, Wu X, Wang Y, Oppenheim JJ, Chen X (2015) Characterization of MT-2 cells as a human regulatory T cell-like cell line. Cell Mol Immunol 12(6):780–782. https://doi.org/10.1038/cmi.2014.123
Hamilton KE, Simmons JG, Ding S, Van Landeghem L, Lund PK (2011) Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells. Mol Cancer Res 9(12):1718–1731. https://doi.org/10.1158/1541-7786
He T, Liu S, Chen S, Ye J, Wu X, Bian Z et al (2018) The p38 MAPK inhibitor SB203580 abrogates tumor necrosis factor-induced proliferative expansion of mouse CD4(+)Foxp3(+) regulatory T cells. Front Immunol 9:1556. https://doi.org/10.3389/fimmu.2018.01556
He J, Li R, Chen Y, Hu Y, Chen X (2019) TNFR2-expressing CD4+Foxp3+ regulatory T cells in cancer immunology and immunotherapy. In: Teplow DB (ed) Progress in molecular biology and translational science. Academic Press, Cambridge, pp 101–117
Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ et al (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135(7):1311–1323. https://doi.org/10.1016/j.cell.2008.10.044
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. https://doi.org/10.1126/science.1079490
Horiuchi T, Mitoma H, Harashima S-i, Tsukamoto H, Shimoda T (2010) Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford) 49(7):1215–1228. https://doi.org/10.1093/rheumatology/keq031
Horwitz DA, Zheng SG, Gray JD (2003) The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol 74(4):471–478. https://doi.org/10.1189/jlb.0503228
Horwitz DA, Pan S, Ou JN, Wang J, Chen M, Gray JD et al (2013) Therapeutic polyclonal human CD8+ CD25+ Fox3+ TNFR2+ PD-L1+ regulatory cells induced ex-vivo. Clin Immunol 149(3):450–463. https://doi.org/10.1016/j.clim.2013.08.007.
Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4(4):387–396. https://doi.org/10.1016/S1074-7613(00)80252-6
Idriss HT, Naismith JH (2000) TNFα and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 50(3):184–195. https://doi.org/10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H
Jacob N, Yang H, Pricop L, Liu Y, Gao X, Zheng SG et al (2009) Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway. J Immunol 182(4):2532–2541. https://doi.org/10.4049/jimmunol.0802948
Kelly ML, Wang M, Crisostomo PR, Abarbanell AM, Herrmann JL, Weil BR et al (2010) TNF receptor 2, not TNF receptor 1 enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia. Shock 33(6):602. https://doi.org/10.1097/SHK.0b013e3181cc0913
Kong N, Lan Q, Su W, Chen M, Wang J, Yang Z et al (2012) Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells. Ann Rheum Dis 71(9):1567–1572. https://doi.org/10.1136/annrheumdis-2011-201052
Kriegler M, Perez C, DeFay K, Albert I, Lu SD (1988) A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53(1):45–53. https://doi.org/10.1016/0092-8674(88)90486-2
Krippner-Heidenreich A, Tubing F, Bryde S, Willi S, Zimmermann G, Scheurich P (2002) Control of receptor-induced signaling complex formation by the kinetics of ligand/receptor interaction. J Biol Chem 277(46):44155–44163. https://doi.org/10.1074/jbc.M207399200
Li P, Zheng Y, Chen X (2017) Drugs for autoimmune inflammatory diseases: from small molecule compounds to anti-TNF biologics. Front Pharmacol 8:460. https://doi.org/10.3389/fphar.2017.00460
Liu C, Workman CJ, Vignali DA (2016) Targeting regulatory T cells in tumors. FEBS J 283(14):2731–2748. https://doi.org/10.1111/febs.13656
Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104(4):487–501. https://doi.org/10.1016/S0092-8674(01)00237-9.
Lu L, Lan Q, Li Z, Zhou X, Gu J, Li Q et al (2014) Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A 111(33):E3432–E3440. https://doi.org/10.1073/pnas.1408780111
Lubrano di Ricco M, Ronin E, Collares D, Divoux J, Gregoire S, Wajant H et al (2020) Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-kappaB. Eur J Immunol. https://doi.org/10.1002/eji.201948393
Mahmud SA, Manlove LS, Schmitz HM, **ng Y, Wang Y, Owen DL et al (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15(5):473–481. https://doi.org/10.1038/ni.2849
Mahoney DJ, Cheung HH, Lejmi Mrad R, Plenchette S, Simard C, Enwere E et al (2008) Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation. Proc Natl Acad Sci U S A 105(33):11778–11783. https://doi.org/10.1073/pnas.0711122105
Maier O, Fischer R, Agresti C, Pfizenmaier K (2013) TNF receptor 2 protects oligodendrocyte progenitor cells against oxidative stress. Biochem Biophys Res Commun 440(2):336–341. https://doi.org/10.1016/j.bbrc.2013.09.083
McMurchy AN, Bushell A, Levings MK, Wood KJ (2011) Moving to tolerance: clinical application of T regulatory cells. Semin Immunol 23(4):304–313. https://doi.org/10.1016/j.smim.2011.04.001
Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114(2):181–190. https://doi.org/10.1016/S0092-8674(03)00521-X
Monaco C, Nanchahal J, Taylor P, Feldmann M (2015) Anti-TNF therapy: past, present and future. Int Immunol 27(1):55–62. https://doi.org/10.1093/intimm/dxu102
van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW et al (2009) Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 58(8):1219–1228. https://doi.org/10.1007/s00262-008-0628-9
Mukai Y, Nakamura T, Yoshikawa M, Yoshioka Y, Tsunoda S-i, Nakagawa S et al (2010) Solution of the structure of the TNF-TNFR2 complex. Sci Signal 3(148):ra83-ra. https://doi.org/10.1126/scisignal.2000954
Munn DH, Sharma MD, Johnson TS (2018) Treg destabilization and reprogramming: implications for cancer immunotherapy. Cancer Res 78(18):5191–5199. https://doi.org/10.1158/0008-5472
Nakayama S, Yokote T, Tsuji M, Akioka T, Miyoshi T, Hirata Y et al (2014) Expression of tumour necrosis factor-α and its receptors in Hodgkin lymphoma. Br J Haematol 167(4):574–577. https://doi.org/10.1111/bjh.13015
Nie Y, He J, Shirota H, Trivett AL, Yang D, Klinman DM et al (2018) Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer. Sci Signal 11(511):eaan0790. https://doi.org/10.1126/scisignal.aan0790
Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127(4):759–767. https://doi.org/10.1002/ijc.25429.
Okubo Y, Mera T, Wang L, Faustman DL (2013) Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci Rep 3:3153. https://doi.org/10.1038/srep03153
Okubo Y, Torrey H, Butterworth J, Zheng H, Faustman DL (2016) Treg activation defect in type 1 diabetes: correction with TNFR2 agonism. Clin Transl Immunol 5(1):e56. https://doi.org/10.1038/cti.2015.43
Panduro M, Benoist C, Mathis D (2016) Tissue Tregs. Annu Rev Immunol 34:609–633. https://doi.org/10.1146/annurev-immunol-032712-095948
Papamichael K, Vogelzang EH, Lambert J, Wolbink G, Cheifetz AS (2019) Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases. Expert Rev Clin Immunol 15(8):837–848. https://doi.org/10.1080/1744666X.2019.1630273
Patel JR, Williams JL, Muccigrosso MM, Liu L, Sun T, Rubin JB et al (2012) Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta Neuropathol 124(6):847–860. https://doi.org/10.1007/s00401-012-1034-0
PCM U, Xuehui H et al (2019) TNFα-signaling modulates the kinase activity of human effector Treg and regulates IL-17A expression. Front Immunol 10:3047. https://doi.org/10.3389/fimmu.2019.03047
Puimège L, Libert C, Van Hauwermeiren F (2014) Regulation and dysregulation of tumor necrosis factor receptor-1. Cytokine Growth Factor Rev 25(3):285–300. https://doi.org/10.1016/j.cytogfr.2014.03.004
Rauert H, Stühmer T, Bargou R, Wajant H, Siegmund D (2011) TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms. Cell Death Dis 2(8):e194-e. https://doi.org/10.1038/cddis.2011.78
Roda G, Jharap B, Neeraj N, Colombel JF (2016) Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol 7:e135. https://doi.org/10.1038/ctg.2015.63
Rothe M, Wong SC, Henzel WJ, Goeddel DV (1994) A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78(4):681–692. https://doi.org/10.1016/0092-8674(94)90532-0
Rothe M, Sarma V, Dixit V, Goeddel D (1995) TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science 269(5229):1424–1427. https://doi.org/10.1126/science.7544915
Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M (2013) Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38(3):541–554. https://doi.org/10.1016/j.immuni.2013.02.007
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164
Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787. https://doi.org/10.1016/j.cell.2008.05.009
Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10(7):490–500. https://doi.org/10.1038/nri2785
Schmidleithner L, Thabet Y, Schönfeld E, Köhne M, Sommer D, Abdullah Z et al (2019) Enzymatic activity of HPGD in Treg cells suppresses tconv cells to maintain adipose tissue homeostasis and prevent metabolic dysfunction. Immunity 50(5):1232–48.e14. https://doi.org/10.1016/j.immuni.2019.03.014
Schmidt A, Oberle N, Krammer PH (2012) Molecular mechanisms of treg-mediated T cell suppression. Front Immunol 3:51. https://doi.org/10.3389/fimmu.2012.00051
Sethi JK, Hotamisligil GS (eds) (1999) The role of TNFα in adipocyte metabolism. Seminars in cell & developmental biology, vol 10. Elsevier, Amsterdam, p 19
Shakoor N, Michalska M, Harris CA, Block JA (2002) Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 359(9306):579–580. https://doi.org/10.1016/S0140-6736(02)07714-0
Sheng Y, Li F, Qin Z (2018) TNF receptor 2 makes tumor necrosis factor a friend of tumors. Front Immunol 9:1170. https://doi.org/10.3389/fimmu.2018.01170
Shevach EM (2018) Foxp3(+) T regulatory cells: still many unanswered questions-A perspective after 20 years of study. Front Immunol 9:1048. https://doi.org/10.3389/fimmu.2018.01048
Sicotte NL, Voskuhl RR (2001) Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 57(10):1885–1888. https://doi.org/10.1212/wnl.57.10.1885
Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM (2003) Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum 48(2):319–324. https://doi.org/10.1002/art.10758
Steeland S, Van Ryckeghem S, Van Imschoot G, De Rycke R, Toussaint W, Vanhoutte L et al (2017) TNFR1 inhibition with a Nanobody protects against EAE development in mice. Sci Rep 7(1):13646. https://doi.org/10.1038/s41598-017-13984-y
Su W, Fan H, Chen M, Wang J, Brand D, He X et al (2012) Induced CD4+ forkhead box protein-positive T cells inhibit mast cell function and established contact hypersensitivity through TGF-beta1. J Allergy Clin Immunol 130(2):444–52.e7. https://doi.org/10.1016/j.jaci.2012.05.011
Su W, Wan Q, Huang J, Han L, Chen X, Chen G et al (2015) Culture medium from TNF-alpha-stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms. J Allergy Clin Immunol 136(2):423–32.e8. https://doi.org/10.1016/j.jaci.2014.12.1926
Taams LS, Palmer DB, Akbar AN, Robinson DS, Brown Z, Hawrylowicz CM (2006) Regulatory T cells in human disease and their potential for therapeutic manipulation. Immunology 118(1):1–9. https://doi.org/10.1111/j.1365-2567.2006.02348.x
Tai X, Cowan M, Feigenbaum L, Singer A (2005) CD28 costimulation of develo** thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6(2):152–162. https://doi.org/10.1038/ni1160
Tartaglia LA, Ayres TM, Wong GH, Goeddel DV (1993) A novel domain within the 55 kd TNF receptor signals cell death. Cell 74(5):845–853. https://doi.org/10.1016/0092-8674(93)90464-2
Togashi Y, Nishikawa H (2017) Regulatory T cells: molecular and cellular basis for Immunoregulation. Curr Top Microbiol Immunol 410:3–27. https://doi.org/10.1007/82_2017_58
Togashi Y, Shitara K, Nishikawa H (2019) Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol 16(6):356–371. https://doi.org/10.1038/s41571-019-0175-7
Torrey H, Butterworth J, Mera T, Okubo Y, Wang L, Baum D et al (2017) Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci Signal 10(462):eaaf8608. https://doi.org/10.1126/scisignal.aaf8608
Torrey H, Khodadoust M, Tran L, Baum D, Defusco A, Kim YH et al (2019) Targeted killing of TNFR2-expressing tumor cells and Tregs by TNFR2 antagonistic antibodies in advanced Sézary syndrome. Leukemia 33(5):1206–1218. https://doi.org/10.1038/s41375-018-0292-9
Tseng WY, Huang YS, Clanchy F, McNamee K, Perocheau D, Ogbechi J et al (2019) TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells. Proc Natl Acad Sci U S A 116(43):21666–21672. https://doi.org/10.1073/pnas.1909687116
Uhlén M, Björling E, Agaton C, Szigyarto CA-K, Amini B, Andersen E et al (2005) A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics 4(12):1920–1932. https://doi.org/10.1074/mcp.M500279-MCP200
Ungewickell A, Bhaduri A, Rios E, Reuter J, Lee CS, Mah A et al (2015) Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2. Nat Genet 47(9):1056–1060. https://doi.org/10.1038/ng.3370
Urbano PCM, Koenen HJPM, Joosten I, He X (2018) An autocrine TNFα–tumor necrosis factor receptor 2 loop promotes epigenetic effects inducing human Treg stability in vitro. Front Immunol 9:573. https://doi.org/10.3389/fimmu.2018.00573
Vanamee ÉS, Faustman DL (2017) TNFR2: A novel target for cancer immunotherapy. Trends Mol Med 23(11):1037–1046. https://doi.org/10.1016/j.molmed.2017.09.007
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714. https://doi.org/10.1038/nrm2970
Vaughan RA, Garcia-Smith R, Trujillo KA, Bisoffi M (2013) Tumor necrosis factor alpha increases aerobic glycolysis and reduces oxidative metabolism in prostate epithelial cells. Prostate 73(14):1538–1546. https://doi.org/10.1002/pros.22703
Wajant H, Scheurich P (2011) TNFR1-induced activation of the classical NF-kappaB pathway. FEBS J 278(6):862–876. https://doi.org/10.1111/j.1742-4658.2011.08015.x
Wajant H, Siegmund D (2019) TNFR1 and TNFR2 in the control of the life and death balance of macrophages. Front Cell Dev Biol 7:91. https://doi.org/10.3389/fcell.2019.00091.
Wang J, Al-Lamki RS (2013) Tumor necrosis factor receptor 2: its contribution to acute cellular rejection and clear cell renal carcinoma. Biomed Res Int 2013:1. https://doi.org/10.1155/2013/821310
Wang A, Creasey A, Ladner M, Lin L, Strickler J, Van Arsdell J et al (1985) Molecular cloning of the complementary DNA for human tumor necrosis factor. Science 228(4696):149–154. https://doi.org/10.1126/science.3856324
Wang L, Du F, Wang X (2008) TNF-α induces two distinct Caspase-8 activation pathways. Cell 133(4):693–703. https://doi.org/10.1016/j.cell.2008.03.036
Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Wallach D, Roufogalis BD et al (1999) A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in ‘reverse signalling’. EMBO J 18(8):2119–2126. https://doi.org/10.1093/emboj/18.8.2119
Williams SK, Fairless R, Maier O, Liermann PC, Pichi K, Fischer R et al (2018) Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis. Sci Rep 8(1):13628. https://doi.org/10.1038/s41598-018-31957-7
Willrich MA, Murray DL, Snyder MR (2015) Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases. Transl Res 165(2):270–282. https://doi.org/10.1016/j.trsl.2014.09.006
Wing JB, Tanaka A, Sakaguchi S (2019) Human FOXP3(+) regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50(2):302–316. https://doi.org/10.1016/j.immuni.2019.01.020
**e P (2013) TRAF molecules in cell signaling and in human diseases. J Mol Signal 8(1):7. https://doi.org/10.1186/1750-2187-8-7
Xu A, Liu Y, Chen W, Wang J, Xue Y, Huang F et al (2016) TGF-beta-induced regulatory T cells directly suppress B cell responses through a noncytotoxic mechanism. J Immunol 196(9):3631–3641. https://doi.org/10.4049/jimmunol.1501740
Yamashita M, Passegué E (2019) TNF-α coordinates hematopoietic stem cell survival and myeloid regeneration. Cell Stem Cell 25(3):357–72.e7. https://doi.org/10.1016/j.stem.2019.05.019
Yan F, Du R, Wei F, Zhao H, Yu J, Wang C et al (2015) Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients. Cancer Immunol Immunother 64(11):1475–1485. https://doi.org/10.1007/s00262-015-1751-z
Yang S, Wang J, Brand DD, Zheng SG (2018) Role of TNF–TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front Immunol 9:784. https://doi.org/10.3389/fimmu.2018.00784
Yang S, **e C, Chen Y, Wang J, Chen X, Lu Z et al (2019) 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(1):27. https://doi.org/10.1038/s41419-018-1266-6
Yang M, Tran L, Torrey H, Song Y, Perkins H, Case K et al (2020) Optimizing TNFR2 antagonism for immunotherapy with tumor microenvironment specificity. J Leukoc Biol 107:1–10. https://doi.org/10.1002/jlb.5ab0320-415rrrrr.
Zaragoza B, Chen X, Oppenheim JJ, Baeyens A, Gregoire S, Chader D et al (2016) Suppressive activity of human regulatory T cells is maintained in the presence of TNF. Nat Med 22(1):16–17. https://doi.org/10.1038/nm.4019
Zhang R, Xu Y, Ekman N, Wu Z, Wu J, Alitalo K et al (2003) Etk/Bmx transactivates vascular endothelial growth factor 2 and recruits phosphatidylinositol 3-kinase to mediate the tumor necrosis factor-induced angiogenic pathway. J Biol Chem 278(51):51267–51276. https://doi.org/10.1074/jbc.M310678200
Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J et al (2012) TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest 122(11):4094–4104. https://doi.org/10.1172/JCI64115.
Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA (2002) Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J Immunol 169(8):4183–4189. https://doi.org/10.4049/jimmunol.169.8.4183
Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25− cells to develop suppressive activity: the role of IL-2, TGF-β, and IL-10. J Immunol 172(9):5213–5221. https://doi.org/10.4049/jimmunol.172.9.5213
Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176(6):3321–3329. https://doi.org/10.4049/jimmunol.176.6.3321
Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA (2007) IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 178(4):2018–2027. https://doi.org/10.4049/jimmunol.178.4.2018
Zhou Z, Gengaro P, Wang W, Wang XQ, Li C, Faubel S et al (2008) Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced cytotoxicity in microvascular endothelial cells. Am J Physiol Renal Physiol 295(4):F932–F941. https://doi.org/10.1152/ajprenal.00066.2008
Zhou Q, Hu Y, Howard OMZ, Oppenheim JJ, Chen X (2014) In vitro generated Th17 cells support the expansion and phenotypic stability of CD4(+)Foxp3(+) regulatory T cells in vivo. Cytokine 65(1):56–64. https://doi.org/10.1016/j.cyto.2013.09.008.
Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307. https://doi.org/10.1038/nri1806
Zou H, Li R, Hu H, Hu Y, Chen X (2018) Modulation of regulatory T cell activity by TNF receptor type II-targeting pharmacological agents. Front Immunol 9:594. https://doi.org/10.3389/fimmu.2018.00594
Acknowledgments
This project was funded by The Science and Technology Development Fund, Macau (File no. 201/2017/A3 and 0056/2019/AFJ) and The University of Macau (File no. MYRG2016-00023-ICMS-QRCM, MYRG2017-00120-ICMS and MYRG2019-00169-ICMS).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Islam, M.S., Yang, Y., Chen, X. (2021). TNF–TNFR2 Signal Plays a Decisive Role in the Activation of CD4+Foxp3+ Regulatory T Cells: Implications in the Treatment of Autoimmune Diseases and Cancer. In: Zheng, SG. (eds) T Regulatory Cells in Human Health and Diseases. Advances in Experimental Medicine and Biology, vol 1278. Springer, Singapore. https://doi.org/10.1007/978-981-15-6407-9_13
Download citation
DOI: https://doi.org/10.1007/978-981-15-6407-9_13
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-15-6406-2
Online ISBN: 978-981-15-6407-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)