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CD137: A checkpoint regulator involved in atherosclerosis

  • Leif Å. Söderström
    Affiliations
    Experimental Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Perioperative Medicine and Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden
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  • Laura Tarnawski
    Affiliations
    Experimental Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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  • Peder S. Olofsson
    Correspondence
    Corresponding author. Karolinska Institutet, Experimental Cardiovascular Medicine, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Solna, 17176, Stockholm, Sweden
    Affiliations
    Experimental Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY, USA
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      Highlights

      • Costimulatory molecules are key regulators of T cell activation and inflammation.
      • CD137 promotes atherosclerosis and vascular inflammation in experimental models.
      • CD137 is expressed in human atherosclerotic lesions.

      Abstract

      Inflammation is associated with atherosclerotic plaque development and precipitation of myocardial infarction and stroke, and anti-inflammatory therapy may reduce disease severity. Costimulatory molecules are key regulators of immune cell activity and inflammation, and are associated with disease development in atherosclerosis. Accumulating evidence indicates that a costimulatory molecule of the Tumor Necrosis Factor Receptor superfamily, the checkpoint regulator CD137, promotes atherosclerosis and vascular inflammation in experimental models. In light of the burgeoning consideration of CD137-targeted therapy in the clinic, it will be important to better understand costimulator immunobiology in development of cardiovascular disease. Here, we review available data on the costimulator CD137 and its potential role in atherosclerosis.

      Keywords

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      References

        • Lozano R.
        • Naghavi M.
        • Foreman K.
        • et al.
        Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
        Lancet. 2012; 380: 2095-2128
        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N. Engl. J. Med. 2005; 352: 1685-1695
        • Libby P.
        • Lichtman A.H.
        • Hansson G.K.
        Immune effector mechanisms implicated in atherosclerosis: from mice to humans.
        Immunity. 2013; 38: 1092-1104
        • Ross R.
        Atherosclerosis–an inflammatory disease.
        N. Engl. J. Med. 1999; 340: 115-126
        • Libby P.
        • Pasterkamp G.
        Requiem for the 'vulnerable plaque'.
        Eur. Heart J. 2015 Nov 14; 36: 2984-2987https://doi.org/10.1093/eurheartj/ehv349
        • Stary H.C.
        • Chandler A.B.
        • Glagov S.
        • et al.
        A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis.
        Am. Heart Assoc. Circ. 1994; 89: 2462-2478
        • Falk E.
        • Nakano M.
        • Bentzon J.F.
        • et al.
        Update on acute coronary syndromes: the pathologists' view.
        Eur. Heart J. 2013; 34: 719-728
        • Ridker P.M.
        • Hennekens C.H.
        • Buring J.E.
        • et al.
        C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
        N. Engl. J. Med. 2000; 342: 836-843
        • Lichtman A.H.
        T cell costimulatory and coinhibitory pathways in vascular inflammatory diseases.
        Front. Physiol. 2012; 3: 18
        • Schonbeck U.
        • Libby P.
        CD40 signaling and plaque instability.
        Circ. Res. 2001; 89: 1092-1103
        • Watts T.H.
        TNF/TNFR family members in costimulation of T cell responses.
        Annu. Rev. Immunol. 2005; 23: 23-68
        • Sakaguchi S.
        Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.
        Nat. Immunol. 2005; 6: 345-352
        • Abbas A.K.
        • Lichtman A.H.
        Basic Immunology: Functions and Disorders of the Immune System.
        Saunders, 2011
        • Nakano M.
        • Fukumoto Y.
        • Satoh K.
        • et al.
        OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization.
        Cardiovasc. Res. 2010; 88: 539-546
        • Sun Y.
        • Lin X.
        • Chen H.M.
        • et al.
        Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis.
        J. Immunol. 2002; 168: 1457-1465
        • Foell J.
        • Strahotin S.
        • O'Neil S.P.
        • et al.
        CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice.
        J. Clin. Invest. 2003; 111: 1505-1518
        • Lutgens E.
        • Gorelik L.
        • Daemen M.J.
        • et al.
        Requirement for CD154 in the progression of atherosclerosis.
        Nat. Med. 1999; 5: 1313-1316
        • Schonbeck U.
        • Sukhova G.K.
        • Shimizu K.
        • et al.
        Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice.
        Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7458-7463
        • Kawai T.
        • Andrews D.
        • Colvin R.B.
        • et al.
        Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand.
        Nat. Med. 2000; 6: 114
        • van Olffen R.W.
        • de Bruin A.M.
        • Vos M.
        • et al.
        CD70-driven chronic immune activation is protective against atherosclerosis.
        J. Innate Immun. 2010; 2: 344-352
        • Snell L.M.
        • Lin G.H.
        • McPherson A.J.
        • et al.
        T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy.
        Immunol. Rev. 2011; 244: 197-217
        • Zheng G.
        • Wang B.
        • Chen A.
        The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells.
        J. Immunol. 2004; 173: 2428-2434
        • Olofsson P.S.
        • Soderstrom L.A.
        • Wagsater D.
        • et al.
        CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice.
        Circulation. 2008; 117: 1292-1301
        • Jeon H.J.
        • Choi J.H.
        • Jung I.H.
        • et al.
        CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice.
        Circulation. 2010; 121: 1124-1133
        • Sharpe A.H.
        • Abbas A.K.
        T-cell costimulation–biology, therapeutic potential, and challenges.
        N. Engl. J. Med. 2006; 355: 973-975
        • Chester C.
        • Sanmamed M.F.
        • Wang J.
        • et al.
        Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies.
        Blood. 2018; 131: 49-57
        • Drenkard D.
        • Becke F.M.
        • Langstein J.
        • et al.
        CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity.
        Faseb. J. 2007; 21: 456-463
        • Teijeira A.
        • Palazon A.
        • Garasa S.
        • et al.
        CD137 on inflamed lymphatic endothelial cells enhances CCL21-guided migration of dendritic cells.
        Faseb. J. 2012; 26: 3380-3392
        • Goodwin R.G.
        • Din W.S.
        • Davis-Smith T.
        • et al.
        Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor.
        Eur. J. Immunol. 1993; 23: 2631-2641
        • Aggarwal B.B.
        Signalling pathways of the TNF superfamily: a double-edged sword.
        Nat. Rev. Immunol. 2003; 3: 745-756
        • Croft M.
        The role of TNF superfamily members in T-cell function and diseases.
        Nat. Rev. Immunol. 2009; 9: 271-285
        • Kwon B.S.
        • Weissman S.M.
        cDNA sequences of two inducible T-cell genes.
        Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1963-1967
        • Pollok K.E.
        • Kim Y.J.
        • Zhou Z.
        • et al.
        Inducible T cell antigen 4-1BB. Analysis of expression and function.
        J. Immunol. 1993; 150: 771-781
        • Kim J.O.
        • Kim H.W.
        • Baek K.M.
        • et al.
        NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells.
        FEBS Lett. 2003; 541: 163-170
        • Shuford W.W.
        • Klussman K.
        • Tritchler D.D.
        • et al.
        4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.
        J. Exp. Med. 1997; 186: 47-55
        • Dawicki W.
        • Bertram E.M.
        • Sharpe A.H.
        • et al.
        4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses.
        J. Immunol. 2004; 173: 5944-5951
        • Goldstein M.J.
        • Kohrt H.E.
        • Houot R.
        • et al.
        Adoptive cell therapy for lymphoma with CD4 T cells depleted of CD137-expressing regulatory T cells.
        Canc. Res. 2012; 72: 1239-1247
        • Futagawa T.
        • Akiba H.
        • Kodama T.
        • et al.
        Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells.
        Int. Immunol. 2002; 14: 275-286
        • Zernecke A.
        Dendritic cells in atherosclerosis: evidence in mice and humans.
        Arterioscler. Thromb. Vasc. Biol. 2015; 35: 763-770
        • Pollok K.E.
        • Kim Y.J.
        • Hurtado J.
        • et al.
        4-1BB T-cell antigen binds to mature B cells and macrophages, and costimulates anti-mu-primed splenic B cells.
        Eur. J. Immunol. 1994; 24: 367-374
        • Shao Z.
        • Schwarz H.
        CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction.
        J. Leukoc. Biol. 2011; 89: 21-29
        • Wang C.
        • Lin G.H.
        • McPherson A.J.
        • et al.
        Immune regulation by 4-1BB and 4-1BBL: complexities and challenges.
        Immunol. Rev. 2009; 229: 192-215
        • Cole J.E.
        • Kassiteridi C.
        • Monaco C.
        Toll-like receptors in atherosclerosis: a 'Pandora's box' of advances and controversies.
        Trends Pharmacol. Sci. 2013; 34: 629-636
        • Kang Y.J.
        • Kim S.O.
        • Shimada S.
        • et al.
        Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages.
        Nat. Immunol. 2007; 8: 601-609
        • Palma C.
        • Binaschi M.
        • Bigioni M.
        • et al.
        CD137 and CD137 ligand constitutively coexpressed on human T and B leukemia cells signal proliferation and survival, International journal of cancer.
        J. Int. Cancer. 2004; 108: 390-398
        • Polte T.
        • Jagemann A.
        • Foell J.
        • et al.
        CD137 ligand prevents the development of T-helper type 2 cell-mediated allergic asthma by interferon-gamma-producing CD8+ T cells.
        Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 2007; 37: 1374-1385
        • Arch R.H.
        • Gedrich R.W.
        • Thompson C.B.
        Tumor necrosis factor receptor-associated factors (TRAFs)–a family of adapter proteins that regulates life and death.
        Gene Dev. 1998; 12: 2821-2830
        • Zarnegar B.J.
        • Wang Y.
        • Mahoney D.J.
        • et al.
        Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK.
        Nat. Immunol. 2008; 9: 1371-1378
        • Vinay D.S.
        • Choi B.K.
        • Bae J.S.
        • et al.
        CD137-deficient mice have reduced NK/NKT cell numbers and function, are resistant to lipopolysaccharide-induced shock syndromes, and have lower IL-4 responses.
        J. Immunol. 2004; 173: 4218-4229
        • Sun Y.
        • Chen H.M.
        • Subudhi S.K.
        • et al.
        Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease.
        Nat. Med. 2002; 8: 1405-1413
        • Vinay D.S.
        • Choi J.H.
        • Kim J.D.
        • et al.
        Role of endogenous 4-1BB in the development of systemic lupus erythematosus.
        Immunology. 2007; 122: 394-400
        • Seo S.K.
        • Choi J.H.
        • Kim Y.H.
        • et al.
        4-1BB-mediated immunotherapy of rheumatoid arthritis.
        Nat. Med. 2004; 10: 1088-1094
        • Foell J.L.
        • Diez-Mendiondo B.I.
        • Diez O.H.
        • et al.
        Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance.
        Immunology. 2004; 113: 89-98
        • Polte T.
        • Foell J.
        • Werner C.
        • et al.
        CD137-mediated immunotherapy for allergic asthma.
        J. Clin. Invest. 2006; 116: 1025-1036
        • Cho Y.S.
        • Kwon B.
        • Lee T.H.
        • et al.
        4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model.
        Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 2006; 36: 377-385
        • Behrendt A.K.
        • Meyer-Bahlburg A.
        • Hansen G.
        CD137 deficiency does not affect development of airway inflammation or respiratory tolerance induction in murine models.
        Clin. Exp. Immunol. 2012; 168: 308-317
        • Gotsman I.
        • Sharpe A.H.
        • Lichtman A.H.
        T-cell costimulation and coinhibition in atherosclerosis.
        Circ. Res. 2008; 103: 1220-1231
        • Jonasson L.
        • Holm J.
        • Skalli O.
        • et al.
        Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque.
        Arteriosclerosis. 1986; 6: 131-138
        • Jung I.H.
        • Choi J.H.
        • Jin J.
        • et al.
        CD137-inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice.
        Faseb. J. 2014; 28: 4779-4791
        • Soderstrom L.A.
        • Jin H.
        • Caravaca A.S.
        • et al.
        Increased carotid artery lesion inflammation upon treatment with the CD137 agonistic antibody 2A.
        Circ. J. Off. J. Jpn. Circ. Soc. 2017; 81: 1945-1952
        • Li Y.
        • Yan J.
        • Wu C.
        • et al.
        CD137–CD137L interaction regulates atherosclerosis via cyclophilin A in apolipoprotein E-deficient mice.
        PLoS One. 2014; 9e88563
        • Yan J.
        • Yin Y.
        • Zhong W.
        • et al.
        CD137 regulates NFATc1 expression in mouse VSMCs through TRAF6/NF-kappaB p65 signaling pathway.
        Mediat. Inflamm. 2015; 2015639780
        • Weng J.
        • Wang C.
        • Zhong W.
        • et al.
        Activation of CD137 signaling promotes angiogenesis in atherosclerosis via modulating endothelial Smad1/5-NFATc1 pathway.
        J. Am. Heart Assoc. 2017; : 6
        • Chen Y.
        • Bangash A.B.
        • Song J.
        • et al.
        Activation of CD137 signaling accelerates vascular calcification in vivo and vitro.
        Int. J. Cardiol. 2017; 230: 198-203
        • Karube A.
        • Suzuki J.
        • Haraguchi G.
        • et al.
        Suppression of neointimal hyperplasia after vascular injury by blocking 4-1BB/4-1BB ligand pathway.
        J. Med. Dent. Sci. 2008; 55: 207-213
        • Kim Y.H.
        • Choi B.K.
        • Shin S.M.
        • et al.
        4-1BB triggering ameliorates experimental autoimmune encephalomyelitis by modulating the balance between Th17 and regulatory T cells.
        J. Immunol. 2011; 187: 1120-1128
        • Ait-Oufella H.
        • Salomon B.L.
        • Potteaux S.
        • et al.
        Natural regulatory T cells control the development of atherosclerosis in mice.
        Nat. Med. 2006; 12: 178-180
        • Robertson S.J.
        • Messer R.J.
        • Carmody A.B.
        • et al.
        CD137 costimulation of CD8+ T cells confers resistance to suppression by virus-induced regulatory T cells.
        J. Immunol. 2008; 180: 5267-5274
        • Barsoumian H.B.
        • Yolcu E.S.
        • Shirwan H.
        4–1BB signaling in conventional T cells drives IL-2 production that overcomes CD4+CD25+FoxP3+ T regulatory cell suppression.
        PLoS One. 2016; 11e0153088
        • Dharmadhikari B.
        • Wu M.
        • Abdullah N.S.
        • et al.
        CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses.
        OncoImmunology. 2016; 5e1113367
        • Yu Y.
        • He Y.
        • Yang T.T.
        • et al.
        Elevated plasma levels and monocyte-associated expression of CD137 ligand in patients with acute atherothrombotic stroke.
        Eur. Rev. Med. Pharmacol. Sci. 2014; 18: 1525-1532
        • Liuzzo G.
        • Biasucci L.M.
        • Trotta G.
        • et al.
        Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events.
        J. Am. Coll. Cardiol. 2007; 50: 1450-1458
        • Liuzzo G.
        • Goronzy J.J.
        • Yang H.
        • et al.
        Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes.
        Circulation. 2000; 101: 2883-2888
        • Liuzzo G.
        • Kopecky S.L.
        • Frye R.L.
        • et al.
        Perturbation of the T-cell repertoire in patients with unstable angina.
        Circulation. 1999; 100: 2135-2139
        • Dumitriu I.E.
        • Baruah P.
        • Finlayson C.J.
        • et al.
        High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome.
        Circ. Res. 2012; 110: 857-869
        • Olofsson P.S.
        Targeting T cell costimulation to prevent atherothrombosis.
        Circ. Res. 2012; 110: 800-801
        • Nakajima T.
        • Schulte S.
        • Warrington K.J.
        • et al.
        T-cell-mediated lysis of endothelial cells in acute coronary syndromes.
        Circulation. 2002; 105: 570-575
        • Yan J.
        • Wang C.
        • Chen R.
        • et al.
        Clinical implications of elevated serum soluble CD137 levels in patients with acute coronary syndrome.
        Clinics. 2013; 68: 193-198
        • Gupta S.
        • Pablo A.M.
        • Jiang X.
        • et al.
        IFN-gamma potentiates atherosclerosis in ApoE knock-out mice.
        J. Clin. Invest. 1997; 99: 2752-2761
        • Ivanov II,
        • McKenzie B.S.
        • Zhou L.
        • et al.
        The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
        Cell. 2006; 126: 1121-1133
        • Veldhoen M.
        • Hocking R.J.
        • Atkins C.J.
        • et al.
        TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
        Immunity. 2006; 24: 179-189
        • Gistera A.
        • Robertson A.K.
        • Andersson J.
        • et al.
        Transforming growth factor-beta signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway.
        Sci. Transl. Med. 2013; 5 (196ra100)
        • Taleb S.
        • Romain M.
        • Ramkhelawon B.
        • et al.
        Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis.
        J. Exp. Med. 2009; 206: 2067-2077
        • de Boer O.J.
        • van der Meer J.J.
        • Teeling P.
        • et al.
        Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions.
        PLoS One. 2007; 2: e779
        • Klingenberg R.
        • Gerdes N.
        • Badeau R.M.
        • et al.
        Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.
        J. Clin. Invest. 2013; 123: 1323-1334
        • Mallat Z.
        • Gojova A.
        • Brun V.
        • et al.
        Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice.
        Circulation. 2003; 108: 1232-1237
        • Gistera A.
        • Hansson G.K.
        The immunology of atherosclerosis, Nature reviews.
        Nephrology. 2017; 13: 368-380
        • van Dijk R.A.
        • Duinisveld A.J.
        • Schaapherder A.F.
        • et al.
        A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis.
        J. Am. Heart Assoc. 2015; : 4
        • Kwon B.S.
        • Kim G.S.
        • Prystowsky M.B.
        • et al.
        Isolation and initial characterization of multiple species of T-lymphocyte subset cDNA clones.
        Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 2896-2900
        • Melero I.
        • Johnston J.V.
        • Shufford W.W.
        • et al.
        NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies.
        Cell. Immunol. 1998; 190: 167-172
        • Kim D.H.
        • Chang W.S.
        • Lee Y.S.
        • et al.
        4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation.
        J. Immunol. 2008; 180: 2062-2068
        • Quek B.Z.
        • Lim Y.C.
        • Lin J.H.
        • et al.
        CD137 enhances monocyte-ICAM-1 interactions in an E-selectin-dependent manner under flow conditions.
        Mol. Immunol. 2010; 47: 1839-1847
        • Palazon A.
        • Teijeira A.
        • Martinez-Forero I.
        • et al.
        Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes.
        Canc. Res. 2011; 71: 801-811
        • Wilcox R.A.
        • Chapoval A.I.
        • Gorski K.S.
        • et al.
        Cutting edge: expression of functional CD137 receptor by dendritic cells.
        J. Immunol. 2002; 168: 4262-4267
        • Pauly S.
        • Broll K.
        • Wittmann M.
        • et al.
        CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers.
        J. Leukoc. Biol. 2002; 72: 35-42
        • Schwarz H.
        • Valbracht J.
        • Tuckwell J.
        • et al.
        ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages.
        Blood. 1995; 85: 1043-1052
        • Kienzle G.
        • von Kempis J.
        CD137 (ILA/4-1BB), expressed by primary human monocytes, induces monocyte activation and apoptosis of B lymphocytes.
        Int. Immunol. 2000; 12: 73-82
        • Zhang X.
        • Voskens C.J.
        • Sallin M.
        • et al.
        CD137 promotes proliferation and survival of human B cells.
        J. Immunol. 2010; 184: 787-795
        • Nakaima Y.
        • Watanabe K.
        • Koyama T.
        • et al.
        CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-kappaB activation.
        PLoS One. 2013; 8e64425
        • Nishimoto H.
        • Lee S.W.
        • Hong H.
        • et al.
        Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor.
        Blood. 2005; 106: 4241-4248
        • Heinisch I.V.
        • Bizer C.
        • Volgger W.
        • et al.
        Functional CD137 receptors are expressed by eosinophils from patients with IgE-mediated allergic responses but not by eosinophils from patients with non-IgE-mediated eosinophilic disorders.
        J. Allergy Clin. Immunol. 2001; 108: 21-28
        • Heinisch I.V.
        • Daigle I.
        • Knopfli B.
        • et al.
        CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils.
        Eur. J. Immunol. 2000; 30: 3441-3446
        • Broll K.
        • Richter G.
        • Pauly S.
        • et al.
        CD137 expression in tumor vessel walls. High correlation with malignant tumors.
        Am. J. Clin. Pathol. 2001; 115: 543-549
        • Langstein J.
        • Michel J.
        • Fritsche J.
        • et al.
        CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling.
        J. Immunol. 1998; 160: 2488-2494