Abstract
CD137 (4-1BB), a member of the tumor necrosis factor receptor (TNFR) superfamily is an activation-inducible type I transmembrane protein receptor expressed on activated T cells, Natural Killer cells (NK), macrophages (Mø), and dendritic cells (DC). Its lig and, 4-1BB-L, is a member of the tumor necrosis factor (TNF) superfamily a type II transmembrane protein that is expressed on antigen presenting cells (APC). Ligand-induced trimerization of CD137 activates multiple signaling pathways in T cells that result in transcriptional activation, enhanced T cell activation and survival. Agonistic anti-CD137 mAbs can replace the need for 4-1BB ligand-mediated receptor crosslinking either in vitro or in vivo. 4-1BB-L specific mAbs can drive cytokine production in APCs; anti-4-1BB ligand mAbs that can block receptor-ligand binding also prevent CD137-mediated T cell costimulation. However, unlike agonistic mAbs to other T cell costimulatory receptors, signaling by anti-CD137 specific mAbs can also suppress the T cellmediated immune responses. CD137 receptor-proximal and downstream signals in T cells have been largely elucidated. However, this is not the case for anti-CD137- induced immune suppression. Given that NK cells and dendritic cells express this receptor, it is not clear whether T cells are the cell targets during anti-CD137 mAb induced immune suppression. In this review we discuss CD137-mediated immune suppression and its role in regulating T-dependent B cell responses and to some extent APC function in normal, autoimmune, and tumor bearing mice.
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
Preview
Unable to display preview. Download preview PDF.
References
Allen, R.C., Armitage, R.J., Conley, M.E., Rosenblatt, H., Jenkins, N.A., Copeland, N.G., Bedell, M.A., Edelhoff, S., Disteche, C.M., Simoneaux, D.K., et al. (1993). CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science, 259, 990–993.
Aruffo, A., Farrington, M., Hollenbaugh, D., Li, X., Milatovich, A., Nonoyama, S., Bajorath, J., Grosmaire, L.S., Stenkamp, R., Neubauer, M., et al. (1993). The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell, 72, 291–300.
Boise, L.H., Minn, A.J., Noel, P.J., June, C.H., Accavitti, M.A., Lindsten, T., and Thompson, C.B. (1995a). CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity, 3, 87–98.
Boise, L.H., Noel, P.J., and Thompson, C.B. (1995b). CD28 and apoptosis. Curr. Opin. Immunol., 7, 620–625.
Bretscher, P., and Cohn, M. (1970). A theory of self-nonself discrimination. Science, 169, 1042–1049.
Broll, K., Richter, G., Pauly, S., Hofstaedter, F., and Schwarz, H. (2001). CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am. J. Clin. Pathol., 115, 543–549.
Brunet, J.F., Denizot, F., Luciani, M.F., Roux-Dosseto, M., Suzan, M., Mattei, M.G., and Golstein, P. (1987). A new member of the immunoglobulin superfamily–CTLA-4. Nature, 328, 267–270.
Cannons, J.L., Lau, P., Ghumman, B., DeBenedette, M.A., Yagita, H., Okumura, K., and Watts, T.H. (2001). 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J. Immunol., 167, 1313–1324.
Chen, C.Y., Del Gatto-Konczak, F., Wu, Z., and Karin, M. (1998). Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science, 280, 1945–1949.
DeBenedette, M.A., Chu, N.R., Pollok, K.E., Hurtado, J., Wade, W.F., Kwon, B.S., and Watts, T.H. (1995). Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J. Exp. Med., 181, 985–992.
DiSanto, J.P., Bonnefoy, J.Y., Gauchat, J.F., Fischer, A., and de Saint Basile, G. (1993). CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature, 361, 541–543.
Durie, F.H., Foy, T.M., Masters, S.R., Laman, J.D., and Noelle, R.J. (1994). The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol. Today, 15, 406–411.
Figdor, C.G., de Vries, I.J., Lesterhuis, W.J., and Melief, C.J. (2004). Dendritic cell immunotherapy: mapping the way. Nat. Med., 10, 475–480.
Foell, J., Strahotin, S., O’Neil, S.P., McCausland, M.M., Suwyn, C., Haber, M., Chander, P.N., Bapat, A.S., Yan, X.J., Chiorazzi, N., et al. (2003). CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J. Clin. Invest., 111, 1505–1518.
Foell, J.L., Diez-Mendiondo, B.I., Diez, O.H., Holzer, U., Ruck, P., Bapat, A.S., Hoffmann, M.K., Mittler, R.S., and Dannecker, G.E. (2004). Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance. Immunology, 113, 89–98.
Foy, T.M., Shepherd, D.M., Durie, F.H., Aruffo, A., Ledbetter, J.A., and Noelle, R.J. (1993). In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J. Exp. Med., 178, 1567–1575.
Futagawa, T., Akiba, H., Kodama, T., Takeda, K., Hosoda, Y., Yagita, H., and Okumura, K. (2002). Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int. Immunol., 14, 275–286.
Gao, W., Kumar, S., Lotze, M.T., Hanning, C., Robbins, P.D., and Gambotto, A. (2003). Innate immunity mediated by the cytokine IL-1 homologue 4 (IL-1H4/IL-1F7) induces IL-12-dependent adaptive and profound antitumor immunity. J. Immunol., 170, 107–113.
Gimmi, C.D., Freeman, G.J., Gribben, J.G., Gray, G., and Nadler, L.M. (1993). Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc. Natl. Acad. Sci. USA, 90, 6586–6590.
Goodwin, R.G., Din, W.S., Davis-Smith, T., Anderson, D.M., Gimpel, S.D., Sato, T.A., Maliszewski, C.R., Brannan, C.I., Copeland, N.G., Jenkins, N.A., et al. (1993). 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., 23, 2631–2641.
Goronzy, J.J., and Weyand, C.M. (1995). T and B cell-dependent pathways in rheumatoid arthritis. Curr. Opin. Rheumatol., 7, 214–221.
Gribben, J.G., Freeman, G.J., Boussiotis, V.A., Rennert, P., Jellis, C.L., Greenfield, E., Barber, M., Restivo, V.A., Jr., Ke, X., Gray, G.S., et al. (1995). CTLA4 mediates antigen-specific apoptosis of human T cells. Proc. Natl. Acad. Sci. USA, 92, 811–815.
Hata, H., Sakaguchi, N., Yoshitomi, H., Iwakura, Y., Sekikawa, K., Azuma, Y., Kanai, C., Moriizumi, E., Nomura, T., Nakamura, T., and Sakaguchi, S. (2004). Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J. Clin. Invest., 114, 582–588.
Hawiger, D., Inaba, K., Dorsett, Y., Guo, M., Mahnke, K., Rivera, M., Ravetch, J.V., Steinman, R.M., and Nussenzweig, M.C. (2001). Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med., 194, 769–779.
Heinisch, I.V., Bizer, C., Volgger, W., and Simon, H.U. (2001). 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., 108, 21–28.
Heinisch, I.V., Daigle, I., Knopfli, B., and Simon, H.U. (2000). CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils. Eur. J. Immunol., 30, 3441–3446.
Houbiers, J.G., van der Burg, S.H., van de Watering, L.M., Tollenaar, R.A., Brand, A., van de Velde, C.J., and Melief, C.J. (1995). Antibodies against p53 are associated with poor prognosis of colorectal cancer. Br. J. Cancer, 72, 637–641.
Hwang, S.Y., Kim, J.Y., Kim, K.W., Park, M.K., Moon, Y., Kim, W.U., and Kim, H.Y. (2004). IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis Res. Ther., 6, R120–128.
Inaba, K., Swiggard, W.J., Inaba, M., Meltzer, J., Mirza, A., Sasagawa, T., Nussenzweig, M.C., and Steinman, R.M. (1995). Tissue distribution of the DEC-205 protein that is detected by the monoclonal antibody NLDC-145. I. Expression on dendritic cells and other subsets of mouse leukocytes. Cell Immunol., 163, 148–156.
Ishihara, K., and Hirano, T. (2002). IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev., 13, 357–368.
Kawabe, T., Naka, T., Yoshida, K., Tanaka, T., Fujiwara, H., Suematsu, S., Yoshida, N., Kishimoto, T., and Kikutani, H. (1994). The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity, 1, 167–178.
Kelsoe, G. (1996). Life and death in germinal centers (redux). Immunity, 4, 107–111.
Kienzle, G., and von Kempis, J. (2000). CD137 (ILA/4-1BB), expressed by primary human monocytes, induces monocyte activation and apoptosis of B lymphocytes. Int. Immunol., 12, 73–82.
Kodama, T., Takeda, K., Shimozato, O., Hayakawa, Y., Atsuta, M., Kobayashi, K., Ito, M., Yagita, H., and Okumura, K. (1999). Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12. Eur. J. Immunol., 29, 1390–1396.
Korthauer, U., Graf, D., Mages, H.W., Briere, F., Padayachee, M., Malcolm, S., Ugazio, A.G., Notarangelo, L.D., Levinsky, R.J., and Kroczek, R.A. (1993). Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature, 361, 539–541.
Kwon, B.S., Kozak, C.A., Kim, K.K., and Pickard, R.T. (1994). Genomic organization and chromosomal localization of the T-cell antigen 4-1BB. J. Immunol., 152, 2256–2262.
Lafferty, K.J., and Cunningham, A.J. (1975). A new analysis of allogeneic interactions. Aust. J. Exp. Biol. Med. Sci., 53, 27–42.
Langstein, J., Michel, J., Fritsche, J., Kreutz, M., Andreesen, R., and Schwarz, H. (1998). CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. J. Immunol., 160, 2488–2494.
Lindstedt, M., Johansson-Lindbom, B., and Borrebaeck, C.A. (2003). Expression of CD137 (4-1BB) on human follicular dendritic cells. Scand. J. Immunol., 57, 305–310.
Linsley, P.S., Brady, W., Grosmaire, L., Aruffo, A., Damle, N.K., and Ledbetter, J.A. (1991). Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J. Exp. Med., 173, 721–730.
Martinet, O., Divino, C.M., Zang, Y., Gan, Y., Mandeli, J., Thung, S., Pan, P.Y., and Chen, S.H. (2002). T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer. Gene. Ther., 9, 786–792.
Mason, U., Aldrich, J., Breedveld, F., Davis, C.B., Elliott, M., Jackson, M., Jorgensen, C., Keystone, E., Levy, R., Tesser, J., et al. (2002). CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J. Rheumatol., 29, 220–229.
Medzhitov, R., and Janeway, C., Jr. (2000). The Toll receptor family and microbial recognition. Trends Microbiol., 8, 452–456.
Medzhitov, R., and Janeway, C.A., Jr. (1999). Innate immune induction of the adaptive immune response. Cold Spring Harb. Symp. Quant. Biol., 64, 429–435.
Melero, I., Bach, N., Hellstrom, K.E., Aruffo, A., Mittler, R.S., and Chen, L. (1998a). Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: Synergy with the CD28 co-stimulatory pathway. Eur. J. Immunol., 28, 1116–1121.
Melero, I., Johnston, J.V., Shufford, W.W., Mittler, R.S., and Chen, L. (1998b). NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell. Immunol., 190, 167–172.
Melero, I., Shuford, W.W., Newby, S.A., Aruffo, A., Ledbetter, J.A., Hellstrom, K.E., Mittler, R.S., and Chen, L. (1997). Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med., 3, 682–685.
Mittler, R.S., Bailey, T.S., Klussman, K., Trailsmith, M.D., and Hoffmann, M.K. (1999). Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J. Exp. Med., 190, 1535–1540.
Mittler, R.S., Foell, J., McCausland, M., Strahotin, S., Niu, L., Bapat, A., and Hewes, L.B. (2004). Anti-CD137 antibodies in the treatment of autoimmune disease and cancer. Immunol. Res., 29, 197–208.
Morrin, M., Kelly, M., Barrett, N., and Delaney, P. (1994). Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. Gut, 35, 1627–1631.
Mueller, D.L., Seiffert, S., Fang, W., and Behrens, T.W. (1996). Differential regulation of bcl-2 and bcl-x by CD3, CD28, and the IL-2 receptor in cloned CD4+ helper T cells. A model for the long-term survival of memory cells. J. Immunol., 156, 1764–1771.
Munn, D.H., Sharma, M.D., Hou, D., Baban, B., Lee, J.R., Antonia, S.J., Messina, J.L., Chandler, P., Koni, P.A., and Mellor, A.L. (2004). Expression of indoleamine 2, 3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest., 114, 280–290.
Nishimoto, N., and Kishimoto, T. (2004). Inhibition of IL-6 for the treatment of inflammatory diseases. Curr. Opin. Pharmacol., 4, 386–391.
Noel, P.J., Boise, L.H., Green, J.M., and Thompson, C.B. (1996). CD28 costimulation prevents cell death during primary T cell activation. J. Immunol., 157, 636–642.
Ohteki, T., Okamoto, S., Nakamura, M., Nemoto, E., and Kumagai, K. (1993). Elevated production of interleukin 6 by hepatic MNC correlates with ICAM-1 expression on the hepatic sinusoidal endothelial cells in autoimmune MRL/lpr mice. Immunol. Lett., 36, 145–152.
Parihar, R., Dierksheide, J., Hu, Y., and Carson, W.E. (2002). IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells. J. Clin. Invest., 110, 983–992.
Pauly, S., Broll, K., Wittmann, M., Giegerich, G., and Schwarz, H. (2002). CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers. J. Leukoc. Biol., 72, 35–42.
Paust, S., and Cantor, H. (2005). Regulatory T cells and autoimmune disease. Immunol. Rev., 204, 195–207.
Pollok, K.E., Kim, Y.J., Zhou, Z., Hurtado, J., Kim, K.K., Pickard, R.T., and Kwon, B.S. (1993). Inducible T cell antigen 4-1BB. Analysis of expression and function. J. Immunol., 150, 771–781.
Qin, Z., Richter, G., Schuler, T., Ibe, S., Cao, X., and Blankenstein, T. (1998). B cells inhibit induction of T cell-dependent tumor immunity. Nat. Med., 4, 627–630.
Radvanyi, L.G., Shi, Y., Vaziri, H., Sharma, A., Dhala, R., Mills, G.B., and Miller, R.G. (1996). CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response. J. Immunol., 156, 1788–1798.
Renshaw, B.R., Fanslow, W.C., 3rd, Armitage, R.J., Campbell, K.A., Liggitt, D., Wright, B., Davison, B.L., and Maliszewski, C.R. (1994). Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med., 180, 1889–1900.
Salomon, B., and Bluestone, J.A. (2001). Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol., 19, 225–252.
Samoilova, E.B., Horton, J.L., Hilliard, B., Liu, T.S., and Chen, Y. (1998). IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: Roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol., 161, 6480–6486.
Scholin, A., Siegbahn, A., Lind, L., Berne, C., Sundkvist, G., Bjork, E., and Karlsson, F.A. (2004). CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes. Diabetes. Metab. Res. Rev., 20, 205–210.
Schwarz, H., Valbracht, J., Tuckwell, J., von Kempis, J., and Lotz, M. (1995). ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. Blood, 85, 1043–1052.
Seo, S.K., Choi, J.H., Kim, Y.H., Kang, W.J., Park, H.Y., Suh, J.H., Choi, B.K., Vinay, D.S., and Kwon, B.S. (2004). 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med., 10, 1088–1094.
Shuford, W.W., Klussman, K., Tritchler, D.D., Loo, D.T., Chalupny, J., Siadak, A.W., Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., et al. (1997). 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., 186, 47–55.
Smyth, M.J., Taniguchi, M., and Street, S.E. (2000). The anti-tumor activity of IL-12: Mechanisms of innate immunity that are model and dose dependent. J. Immunol., 165, 2665–2670.
Snapper, C.M., and Mond, J.J. (1993). Towards a comprehensive view of immunoglobulin class switching. Immunol. Today, 14, 15–17.
Snapper, C.M., and Mond, J.J. (1996). A model for induction of T cell-independent humoral immunity in response to polysaccharide antigens. J. Immunol., 157, 2229–2233.
Steinman, R.M. (1991). The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol., 9, 271–296.
Steinman, R.M., Inaba, K., Turley, S., Pierre, P., and Mellman, I. (1999). Antigen capture, processing, and presentation by dendritic cells: Recent cell biological studies. Hum. Immunol., 60, 562–567.
Steinman, R.M., and Nussenzweig, M.C. (2002). Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. USA, 99, 351–358.
Summers, K.L., Hock, B.D., McKenzie, J.L., and Hart, D.N. (2001). Phenotypic characterization of five dendritic cell subsets in human tonsils. Am. J. Pathol., 159, 285–295.
Sun, Y., Chen, H.M., Subudhi, S.K., Chen, J., Koka, R., Chen, L., and Fu, Y.X. (2002). Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat. Med., 8, 1405–1413.
Suzuki, H., Yasukawa, K., Saito, T., Narazaki, M., Hasegawa, A., Taga, T., and Kishimoto, T. (1993). Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal. Eur. J. Immunol., 23, 1078–1082.
Takahashi, C., Mittler, R.S., and Vella, A.T. (1999). Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. J. Immunol., 162, 5037–5040.
Tang, B., Matsuda, T., Akira, S., Nagata, N., Ikehara, S., Hirano, T., and Kishimoto, T. (1991). Age-associated increase in interleukin 6 in MRL/lpr mice. Int. Immunol., 3, 273–278.
Uekusa, Y., Gao, P., Yamaguchi, N., Tomura, M., Mukai, T., Nakajima, C., Iwasaki, M., Takeuchi, N., Tsujimura, T., Nakazawa, M., et al. (2002). A role for endogenous IL-12 in tumor immunity: IL-12 is required for the acquisition of tumor-migratory capacity by T cells and the development of T cell-accepting capacity in tumor masses. J. Leukoc. Biol., 72, 864–873.
van Essen, D., Kikutani, H., and Gray, D. (1995). CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature, 378, 620–623.
Van Parijs, L., Ibraghimov, A., and Abbas, A.K. (1996). The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity, 4, 321–328.
Viola, A., and Lanzavecchia, A. (1996). T cell activation determined by T cell receptor number and tunable thresholds. Science, 273, 104–106.
Vozarova, B., Weyer, C., Hanson, K., Tataranni, P.A., Bogardus, C., and Pratley, R.E. (2001). Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes. Res., 9, 414–417.
Wagner, U., Pierer, M., Wahle, M., Moritz, F., Kaltenhauser, S., and Hantzschel, H. (2004). Ex vivo homeostatic proliferation of CD4+ T cells in rheumatoid arthritis is dysregulated and driven by membrane-anchored TNFalpha. J. Immunol., 173, 2825–2833.
Walunas, T.L., Bakker, C.Y., and Bluestone, J.A. (1996). CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med., 183, 2541–2550.
Waterhouse, P., Penninger, J.M., Timms, E., Wakeham, A., Shahinian, A., Lee, K.P., Thompson, C.B., Griesser, H., and Mak, T.W. (1995). Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science, 270, 985–988.
Watts, T.H. (2005). Tnf/Tnfr family members in costimulation of T cell responses. Annu. Rev. Immunol., 23, 23–68.
Wei, W.Z., Morris, G.P., and Kong, Y.C. (2004). Anti-tumor immunity and autoimmunity: A balancing act of regulatory T cells. Cancer Immunol. Immunother., 53, 73–78.
Wilcox, R.A., Chapoval, A.I., Gorski, K.S., Otsuji, M., Shin, T., Flies, D.B., Tamada, K., Mittler, R.S., Tsuchiya, H., Pardoll, D.M., and Chen, L. (2002). Cutting edge: Expression of functional CD137 receptor by dendritic cells. J. Immunol., 168, 4262–4267.
Wofsy, D. (1988). The role of Lyt-2+ T cells in the regulation of autoimmunity in murine lupus. J. Autoimmun., 1, 207–217.
Wofsy, D. (1993). Treatment of murine lupus with anti-CD4 monoclonal antibodies. Immunol. Ser., 59, 221–236.
Wofsy, D., Chiang, N.Y., Greenspan, J.S., and Ermak, T.H. (1988). Treatment of murine lupus with monoclonal antibody to L3T4. I. Effects on the distribution and function of lymphocyte subsets and on the histopathology of autoimmune disease. J. Autoimmun., 1, 415–431.
Wofsy, D., and Seaman, W.E. (1985). Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J. Exp. Med., 161, 378–391.
Wofsy, D., and Seaman, W.E. (1987). Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. J. Immunol., 138, 3247–3253.
Wolf, H., Muller, Y., Salmen, S., Wilmanns, W., and Jung, G. (1994). Induction of anergy in resting human T lymphocytes by immobilized anti-CD3 antibodies. Eur. J. Immunol., 24, 1410–1417.
Xu, J., Foy, T.M., Laman, J.D., Elliott, E.A., Dunn, J.J., Waldschmidt, T.J., Elsemore, J., Noelle, R.J., and Flavell, R.A. (1994). Mice deficient for the CD40 ligand. Immunity, 1, 423–431.
Zhou, Z., Kim, S., Hurtado, J., Lee, Z.H., Kim, K.K., Pollok, K.E., and Kwon, B.S. (1995). Characterization of human homologue of 4-1BB and its ligand. Immunol. Lett., 45, 67–73.
Zhu, G., Flies, D.B., Tamada, K., Sun, Y., Rodriguez, M., Fu, Y.X., and Chen, L. (2001). Progressive depletion of peripheral B lymphocytes in 4-1BB (CD137) ligand/I-Ealpha)-transgenic mice. J. Immunol., 167, 2671–2676.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer
About this chapter
Cite this chapter
Mittler, R.S., Niu, L., Hewes, B., Foell, J. (2006). Regulation of T Cell-Dependent Humoral Immunity Through CD137 (4-1BB) Mediated Signals. In: Chen, L. (eds) CD137 Pathway: Immunology and Diseases. Springer, Boston, MA. https://doi.org/10.1007/0-387-32829-7_5
Download citation
DOI: https://doi.org/10.1007/0-387-32829-7_5
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-387-31322-1
Online ISBN: 978-0-387-32829-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)