• Jayakumar R. Nair
  • Cheryl Rozanski
  • Kelvin P. Lee*
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 633)

1 Introduction

The concept of a costimulatory signal requirement for immune cell activation has been attributed to Bretscher and Cohn,7 who first proposed that B cell activation required two signals. This model was subsequently modified by Lafferty and Cunningham for T cell activation and allograft rejection.7,34 For naïve T cell activation, signal one is delivered by the T cell receptor (TCR) binding to cognate antigen presented by major histocompatibility complex (MHC) molecules on professional antigen presentation cells (APCs). The second signal is delivered by costimulatory receptor binding to its ligand(s) on the APC. While the costimulatory signal alone characteristically has no effect on T cells, in combination with a signal 1 it has been clearly shown to enhance cytokine secretion, proliferation, metabolic fitness, and survival during T cell activation.

The prototypic costimulatory receptor is CD28, and its effect on T cell activation has been extensively characterized....


Multiple Myeloma Myeloma Cell Myeloma Cell Line Bone Marrow Microenvironment CD28 Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Almeida, J., Orfao, A., Ocqueteau, M., Mateo, G., Corral, M., Caballero, M. D., Blade, J., Moro, M. J., Hernandez, J. San Miguel, J. F., 1999, High-sensitive immunophenotyping and DNA ploidy studies for the investigation of minimal residual disease in multiple myeloma, Br J Haematol 107:(1)121–131CrossRefPubMedGoogle Scholar
  2. 2.
    Anderson, K. C., Kyle, R. A., Dalton, W. S., Landowski, T., Shain, K., Jove, R., Hazlehurst, L. and Berenson, J., 2000, Multiple myeloma: new insights and therapeutic approaches, Hematology (Am Soc Hematol Educ Program) 147–165<bib id="bib2_6"> <no>2.</no> <otherref>Anderson, K. C., Kyle, R. A., Dalton, W. S., Landowski, T., Shain, K., Jove, R., Hazlehurst, L. and Berenson, J., 2000, Multiple myeloma: new insights and therapeutic approaches, <Emphasis Type="Italic">Hematology (Am Soc Hematol Educ Program)</Emphasis> 147&#x2013;165</otherref> </bib> Google Scholar
  3. 3.
    Aruffo, A. Seed, B., 1987, Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system, Proc Natl Acad Sci USA 84:(23)8573–8577CrossRefPubMedGoogle Scholar
  4. 4.
    Bahlis, N. J., King, A. M., Kolonias, D., Carlson, L. M., Liu, H. Y., Hussein, M. A., Terebelo, H. R., Byrne, G. E., Jr.Levine, B. L., Boise, L. H. Lee, K. P., 2007, CD28-mediated regulation of multiple myeloma cell proliferation and survival, Blood 109:(11)5002–5010CrossRefPubMedGoogle Scholar
  5. 5.
    Balazs, M., Martin, F., Zhou, T. Kearney, J., 2002, Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses, Immunity 17:(3)341–352CrossRefPubMedGoogle Scholar
  6. 6.
    Bisping, G., Leo, R., Wenning, D., Dankbar, B., Padro, T., Kropff, M., Scheffold, C., Kroger, M., Mesters, R. M., Berdel, W. E. Kienast, J., 2003, Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma, Blood 101:(7)2775–2783CrossRefPubMedGoogle Scholar
  7. 7.
    Bretscher, P. Cohn, M., 1970, A theory of self-nonself discrimination, Science 169:(950)1042–1049CrossRefPubMedGoogle Scholar
  8. 8.
    Brunet, J. F., Denizot, F., Luciani, M. F., Roux-Dosseto, M., Suzan, M., Mattei, M. G. Golstein, P., 1987, A new member of the immunoglobulin superfamily–CTLA-4, Nature 328:(6127)267–270CrossRefPubMedGoogle Scholar
  9. 9.
    Burr, J. S., Savage, N. D., Messah, G. E., Kimzey, S. L., Shaw, A. S., Arch, R. H. Green, J. M., 2001, Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL, J Immunol 166:(9)5331–5335PubMedGoogle Scholar
  10. 10.
    Corthay, A., Skovseth, D. K., Lundin, K. U., Rosjo, E., Omholt, H., Hofgaard, P. O., Haraldsen, G. Bogen, B., 2005, Primary antitumor immune response mediated by CD4+ T cells, Immunity 22:(3)371–383CrossRefPubMedGoogle Scholar
  11. 11.
    Damiano, J. S., Cress, A. E., Hazlehurst, L. A., Shtil, A. A. Dalton, W. S., 1999, Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines, Blood 93:(5)1658–1667PubMedGoogle Scholar
  12. 12.
    Dankbar, B., Padro, T., Leo, R., Feldmann, B., Kropff, M., Mesters, R. M., Serve, H., Berdel, W. E. Kienast, J., 2000, Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma, Blood 95:(8)2630–2636PubMedGoogle Scholar
  13. 13.
    Delogu, A., Schebesta, A., Sun, Q., Aschenbrenner, K., Perlot, T. Busslinger, M., 2006, Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells, Immunity 24:(3)269–281CrossRefPubMedGoogle Scholar
  14. 14.
    Drexler, H. G. Matsuo, Y., 2000, Malignant hematopoietic cell lines: in vitro models for the study of multiple myeloma and plasma cell leukemia, Leukemia Res 24:(8)681–703CrossRefGoogle Scholar
  15. 15.
    Dubois, B., Barthelemy, C., Durand, I., Liu, Y. J., Caux, C. Briere, F., 1999, Toward a role of dendritic cells in the germinal center reaction: triggering of B cell proliferation and isotype switching, J Immunol 162:(6)3428–3436PubMedGoogle Scholar
  16. 16.
    Dubois, B., Massacrier, C., Vanbervliet, B., Fayette, J., Briere, F., Banchereau, J. Caux, C., 1998, Critical role of IL-12 in dendritic cell-induced differentiation of naive B lymphocytes, J Immunol 161:(5)2223–2231PubMedGoogle Scholar
  17. 17.
    Fallarino, F., Vacca, C., Orabona, C., Belladonna, M. L., Bianchi, R., Marshall, B., Keskin, D. B., Mellor, A. L., Fioretti, M. C., Grohmann, U. Puccetti, P., 2002, Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells, Int Immunol 14:(1)65–68CrossRefPubMedGoogle Scholar
  18. 18.
    Fayette, J., Durand, I., Bridon, J. M., Arpin, C., Dubois, B., Caux, C., Liu, Y. J., Banchereau, J. Briere, F., 1998, Dendritic cells enhance the differentiation of naive B cells into plasma cells in vitro, Scand J Immunol 48:(6)563–570CrossRefPubMedGoogle Scholar
  19. 19.
    Frauwirth, K. A., Riley, J. L., Harris, M. H., Parry, R. V., Rathmell, J. C., Plas, D. R., Elstrom, R. L., June, C. H. Thompson, C. B., 2002, The CD28 signaling pathway regulates glucose metabolism, Immunity 16:(6)769–777CrossRefPubMedGoogle Scholar
  20. 20.
    Gray Parkin, K., Stephan, R. P., Apilado, R. G., Lill-Elghanian, D. A., Lee, K. P., Saha, B. Witte, P. L., 2002, Expression of CD28 by bone marrow stromal cells and its involvement in B lymphopoiesis, J Immunol 169:(5)2292–2302PubMedGoogle Scholar
  21. 21.
    Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C. Puccetti, P., 2002, CTLA-4-Ig regulates tryptophan catabolism in vivo, Nat Immunol 3:(11)1097–1101CrossRefPubMedGoogle Scholar
  22. 22.
    Hallek, M., Bergsagel, P. L. Anderson, K. C., 1998, Multiple myeloma: increasing evidence for a multistep transformation process, Blood 91:(1)3–21PubMedGoogle Scholar
  23. 23.
    Hazlehurst, L. A., Damiano, J. S., Buyuksal, I., Pledger, W. J. Dalton, W. S., 2000, Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR), Oncogene 19:(38)4319–4327CrossRefPubMedGoogle Scholar
  24. 24.
    Horspool, J. H., Perrin, P. J., Woodcock, J. B., Cox, J. H., King, C. L., June, C. H., Harlan, D. M., St Louis, D. C. Lee, K. P., 1998, Nucleic acid vaccine-induced immune responses require CD28 costimulation and are regulated by CTLA4, J Immunol 160:(6)2706–2714PubMedGoogle Scholar
  25. 25.
    Hwu, P., Du, M. X., Lapointe, R., Do, M., Taylor, M. W. Young, H. A., 2000, Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation, J Immunol 164:(7)3596–3599PubMedGoogle Scholar
  26. 26.
    June, C. H., Ledbetter, J. A., Gillespie, M. M., Lindsten, T. Thompson, C. B., 1987, T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression, Mol Cell Biol 7:(12)4472–4481PubMedGoogle Scholar
  27. 27.
    June, C. H., Vandenberghe, P. Thompson, C. B., 1994, The CD28 and CTLA-4 receptor family, Chem Immunol 59:62–90PubMedCrossRefGoogle Scholar
  28. 28.
    Kornbluth, J., 1995, Potential role of CD28-B7 interactions in the growth of myeloma plasma cells, Curr Top Microbiol Immunol 194:43–49PubMedGoogle Scholar
  29. 29.
    Kozbor, D., Moretta, A., Messner, H. A., Moretta, L. Croce, C. M., 1987, Tp44 molecules involved in antigen-independent T cell activation are expressed on human plasma cells, J Immunol 138:(12)4128–4132PubMedGoogle Scholar
  30. 30.
    Kukreja, A., Hutchinson, A., Dhodapkar, K., Mazumder, A., Vesole, D., Angitapalli, R., Jagannath, S. Dhodapkar, M. V., 2006, Enhancement of clonogenicity of human multiple myeloma by dendritic cells, J Exp Med 203:(8)1859–1865CrossRefPubMedGoogle Scholar
  31. 31.
    Kukreja, A., Hutchinson, A., Mazumder, A., Vesole, D., Angitapalli, R., Jagannath,S., O'Connor O, A. Dhodapkar, M. V., 2007, Bortezomib disrupts tumour-dendritic cell interactions in myeloma and lymphoma: therapeutic implications, Br J Haematol 136:(1)106–110CrossRefPubMedGoogle Scholar
  32. 32.
    Kushnir, N., Liu, L. MacPherson, G. G., 1998, Dendritic cells and resting B cells form clusters in vitro and in vivo: T cell independence, partial LFA-1 dependence, and regulation by cross-linking surface molecules, J Immunol 160:(4)1774–1781PubMedGoogle Scholar
  33. 33.
    Kyle, R. A. Rajkumar, S. V., 2004, Multiple myeloma, N Engl J Med 351:(18)1860–1873CrossRefPubMedGoogle Scholar
  34. 34.
    Lafferty, K. J., Warren, H. S., Woolnough, J. A. Talmage, D. W., 1978, Immunological induction of T lymphocytes: role of antigen and the lymphocyte costimulator, Blood Cells 4:(3)395–406PubMedGoogle Scholar
  35. 35.
    Landowski, T. H., Olashaw, N. E., Agrawal, D. Dalton, W. S., 2003, Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells, Oncogene 22:(16)2417–2421CrossRefPubMedGoogle Scholar
  36. 36.
    Lee, J. R., Dalton, R. R., Messina, J. L., Sharma, M. D., Smith, D. M., Burgess, R. E., Mazzella, F., Antonia, S. J., Mellor, A. L. Munn, D. H., 2003, Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma, Lab Invest 83:(10)1457–1466CrossRefPubMedGoogle Scholar
  37. 37.
    Lee, K. P., Taylor, C., Petryniak, B., Turka, L. A., June, C. H. Thompson, C. B., 1990, The genomic organization of the CD28 gene. Implications for the regulation of CD28 mRNA expression and heterogeneity, J Immunol 145:(1)344–352PubMedGoogle Scholar
  38. 38.
    Lindstein, T., June, C. H., Ledbetter, J. A., Stella, G. Thompson, C. B., 1989, Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway, Science 244:(4902)339–343CrossRefPubMedGoogle Scholar
  39. 39.
    Linsley, P. S., Brady, W., Urnes, M., Grosmaire, L. S., Damle, N. K. Ledbetter, J. A., 1991, CTLA-4 is a second receptor for the B cell activation antigen B7, J Exp Med 174:(3)561–569CrossRefPubMedGoogle Scholar
  40. 40.
    Lokhorst, H. M., Lamme, T., Smet, M., de Klein, S., Weger, R. A., de Oers, R. van Bloem, A. C., 1994, Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures, Blood 84:(7)2269–2277PubMedGoogle Scholar
  41. 41.
    Lokhorst, H. M., Sonneveld, P. Verdonck, L. F., 1999, Intensive treatment for multiple myeloma: where do we stand? Br J Haematol 106:(1)18–27CrossRefPubMedGoogle Scholar
  42. 42.
    Martin, P. J., Ledbetter, J. A., Morishita, Y., June, C. H., Beatty, P. G. Hansen, J. A., 1986, A 44 kilodalton cell surface homodimer regulates interleukin 2 production by activated human T lymphocytes, J Immunol 136:(9)3282–3287PubMedGoogle Scholar
  43. 43.
    Mateo, G., Castellanos, M., Rasillo, A., Gutierrez, N. C., Montalban, M. A., Martin, M. L., Hernandez, J. M., Lopez-Berges, M. C., Montejano, L., Blade, J., Mateos, M. V., Sureda, A., Rubia, J., de la Diaz-Mediavilla, J., Pandiella, A., Lahuerta, J. J., Orfao, A. San Miguel, J. F., 2005, Genetic abnormalities and patterns of antigenic expression in multiple myeloma, Clin Cancer Res 11:(10)3661–3667CrossRefPubMedGoogle Scholar
  44. 44.
    Matsuo, Y., Drexler, H. G., Harashima, A., Okochi, A., Hasegawa, A., Kojima, K. Orita, K., 2004, Induction of CD28 on the new myeloma cell line MOLP-8 with t(11;14)(q13;q32) expressing delta/lambda type immunoglobulin, Leukemia Res 28:(8)869–877CrossRefGoogle Scholar
  45. 45.
    Mellor, A. L., Chandler, P., Lee, G. K., Johnson, T., Keskin, D. B., Lee, J. Munn, D. H., 2002, Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy, J Reprod Immunol 57:(1–2)143–150CrossRefPubMedGoogle Scholar
  46. 46.
    Mellor, A. L. Munn, D. H., 1999, Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:(10)469–473CrossRefPubMedGoogle Scholar
  47. 47.
    Minges Wols, H. A., Underhill, G. H., Kansas, G. S. Witte, P. L., 2002, The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity, J Immunol 169:(8)4213–4221PubMedGoogle Scholar
  48. 48.
    Moreaux, J., Legouffe, E., Jourdan, E., Quittet, P., Reme, T., Lugagne, C., Moine, P., Rossi, J. F., Klein, B. Tarte, K., 2004, BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone, Blood 103:(8)3148–3157CrossRefPubMedGoogle Scholar
  49. 49.
    Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. G., Johnson, T. S., Keskin, D. B., Marshall, B., Chandler, P., Antonia, S. J., Burgess, R., Slingluff, C. L., Jr.Mellor, A. L., 2002, Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase, Science 297:(5588)1867–1870CrossRefPubMedGoogle Scholar
  50. 50.
    Munn, D. H., Sharma, M. D. Mellor, A. L., 2004, Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells, J Immunol 172:(7)4100–4110PubMedGoogle Scholar
  51. 51.
    Orabona, C., Grohmann, U., Belladonna, M. L., Fallarino, F., Vacca, C., Bianchi, R., Bozza, S., Volpi, C., Salomon, B. L., Fioretti, M. C., Romani, L. Puccetti, P., 2004, CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86, Nat Immunol 5:(11)1134–1142CrossRefPubMedGoogle Scholar
  52. 52.
    Pellat-Deceunynck, C., Bataille, R., Robillard, N., Harousseau, J. L., Rapp, M. J., Juge-Morineau, N., Wijdenes, J. Amiot, M., 1994, Expression of CD28 and CD40 in human myeloma cells: a comparative study with normal plasma cells, Blood 84:(8)2597–2603PubMedGoogle Scholar
  53. 53.
    Pope, B., Brown, R. D., Gibson, J., Yuen, E. Joshua, D., 2000, B7-2-positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy, Blood 96:(4)1274–1279PubMedGoogle Scholar
  54. 54.
    Qiu, Y. H., Sun, Z. W., Shi, Q., Su, C. H., Chen, Y. J., Shi, Y. J., Tao, R., Ge, Y. Zhang, X. G., 2005, Apoptosis of multiple myeloma cells induced by agonist monoclonal antibody against human CD28, Cell Immunol 236:(1–2)154–160CrossRefPubMedGoogle Scholar
  55. 55.
    Rettig, M. B., Ma, H. J., Vescio, R. A., Pold, M., Schiller, G., Belson, D., Savage, A., Nishikubo, C., Wu, C., Fraser, J., Said, J. W. Berenson, J. R., 1997, Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients, Science 276:(5320)1851–1854CrossRefPubMedGoogle Scholar
  56. 56.
    Robillard, N., Jego, G., Pellat-Deceunynck, C., Pineau, D., Puthier, D., Mellerin, M. P., Barille, S., Rapp, M. J., Harousseau, J. L., Amiot, M. Bataille, R., 1998, CD28, a marker associated with tumoral expansion in multiple myeloma, Clin Cancer Res 4:(6)1521–1526PubMedGoogle Scholar
  57. 57.
    Rudd, C. E. Raab, M., 2003, Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation, Immunol Rev 192:32–41CrossRefPubMedGoogle Scholar
  58. 58.
    Sadra, A., Cinek, T., Arellano, J. L., Shi, J., Truitt, K. E. Imboden, J. B., 1999, Identification of tyrosine phosphorylation sites in the CD28 cytoplasmic domain and their role in the costimulation of Jurkat T cells, J Immunol 162:(4)1966–1973PubMedGoogle Scholar
  59. 59.
    Said, J. W., Rettig, M. R., Heppner, K., Vescio, R. A., Schiller, G., Ma, H. J., Belson, D., Savage, A., Shintaku, I. P., Koeffler, H. P., Asou, H., Pinkus, G., Pinkus, J., Schrage, M., Green, E. Berenson, J. R., 1997, Localization of Kaposi's sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma, Blood 90:(11)4278–4282PubMedGoogle Scholar
  60. 60.
    Santiago-Schwarz, F., Tucci, J. Carsons, S. E., 1996, Endogenously produced interleukin 6 is an accessory cytokine for dendritic cell hematopoiesis, Stem Cells 14:(2)225–231CrossRefPubMedGoogle Scholar
  61. 61.
    Shahinian, A., Pfeffer, K., Lee, K. P., Kundig, T. M., Kishihara, K., Wakeham, A., Kawai, K., Ohashi, P. S., Thompson, C. B. Mak, T. W., 1993, Differential T cell costimulatory requirements in CD28-deficient mice, Science 261:(5121)609–612CrossRefPubMedGoogle Scholar
  62. 62.
    Shapiro, V. S., Mollenauer, M. N. Weiss, A., 2001, Endogenous CD28 expressed on myeloma cells up-regulates interleukin-8 production: implications for multiple myeloma progression, Blood 98:(1)187–193CrossRefPubMedGoogle Scholar
  63. 63.
    Sharpe, A. H. Freeman, G. J., 2002, The B7-CD28 superfamily, Nat Rev Immunol 2:(2)116–126CrossRefPubMedGoogle Scholar
  64. 64.
    Thompson, C. B., Lindsten, T., Ledbetter, J. A., Kunkel, S. L., Young, H. A., Emerson, S. G., Leiden, J. M. June, C. H., 1989, CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines, Proc Natl Acad Sci USA 86:(4)1333–1337CrossRefPubMedGoogle Scholar
  65. 65.
    Donk, N. W., van de Lokhorst, H. M. Bloem, A. C., 2005, Growth factors and antiapoptotic signaling pathways in multiple myeloma, Leukemia 19:(12)2177–2185CrossRefPubMedGoogle Scholar
  66. 66.
    Venuprasad, K., Parab, P., Prasad, D. V., Sharma, S., Banerjee, P. R., Deshpande, M., Mitra, D. K., Pal, S., Bhadra, R., Mitra, D. Saha, B., 2001, Immunobiology of CD28 expression on human neutrophils. I. CD28 regulates neutrophil migration by modulating CXCR-1 expression, Eur J Immunol 31:(5)1536–1543CrossRefPubMedGoogle Scholar
  67. 67.
    Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H. Mak, T. W., 1995, Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4, Science 270:(5238)985–988CrossRefPubMedGoogle Scholar
  68. 68.
    Wykes, M. MacPherson, G., 2000, Dendritic cell-B-cell interaction: dendritic cells provide B cells with CD40-independent proliferation signals and CD40-dependent survival signals, Immunology 100:(1)1–3CrossRefPubMedGoogle Scholar
  69. 69.
    Zhang, X. G., Olive, D., Devos, J., Rebouissou, C., Ghiotto-Ragueneau, M., Ferlin, M. Klein, B., 1998, Malignant plasma cell lines express a functional CD28 molecule, Leukemia 12:(4)610–618CrossRefPubMedGoogle Scholar
  70. 70.
    Zhou, L. J. Tedder, T. F., 1995, A distinct pattern of cytokine gene expression by human CD83+ blood dendritic cells, Blood 86:(9)3295–3301PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jayakumar R. Nair
    • 1
  • Cheryl Rozanski
  • Kelvin P. Lee*
  1. 1.Department of ImmunologyRoswell Park Cancer InstituteBuffaloUSA

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