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. 1991 Aug 1;88(15):6575–6579. doi: 10.1073/pnas.88.15.6575

B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2.

C D Gimmi 1, G J Freeman 1, J G Gribben 1, K Sugita 1, A S Freedman 1, C Morimoto 1, L M Nadler 1
PMCID: PMC52129  PMID: 1650475

Abstract

Occupancy of the T-cell receptor complex does not appear to be a sufficient stimulus to induce a T-cell-mediated immune response. Increasing evidence suggests that cognate cell-cell interaction between an activated T cell and an antigen-presenting cell may provide such a stimulus. A candidate T-cell surface molecule for this costimulatory signal is the T-cell-restricted CD28 antigen. Following crosslinking with anti-CD28 mAb, suboptimally stimulated CD28+ T cells show increased proliferation and markedly increased secretion of a subset of lymphokines. Recently, the B-cell surface activation antigen B7 was shown to be a natural ligand for the CD28 molecule, and both B7 and CD28 are members of the immunoglobulin superfamily. Here we report that B7-transfected CHO cells can induce suboptimally activated CD28+ T cells to proliferate and secrete high levels of interleukin 2. The response is identical whether T cells are submitogenically stimulated with either phorbol myristate acetate or anti-CD3 to activate the T cells. This response is specific and can be totally abrogated with anti-B7 monoclonal antibody. As has previously been observed for anti-CD28 monoclonal antibody, B7 ligation induced secretion of interleukin 2 but not interleukin 4. We have previously demonstrated that B7 expression is restricted to activated B lymphocytes and interferon gamma-activated monocytes. Since these two cellular populations are involved in antigen presentation as well as cognate interaction with T lymphocytes, B7 is likely to represent a central constimulatory signal that is capable of amplifying an immune response.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aruffo A., Seed B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8573–8577. doi: 10.1073/pnas.84.23.8573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bierer B. E., Peterson A., Barbosa J., Seed B., Burakoff S. J. Expression of the T-cell surface molecule CD2 and an epitope-loss CD2 mutant to define the role of lymphocyte function-associated antigen 3 (LFA-3) in T-cell activation. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1194–1198. doi: 10.1073/pnas.85.4.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Damle N. K., Doyle L. V., Grosmaire L. S., Ledbetter J. A. Differential regulatory signals delivered by antibody binding to the CD28 (Tp44) molecule during the activation of human T lymphocytes. J Immunol. 1988 Mar 15;140(6):1753–1761. [PubMed] [Google Scholar]
  4. Damle N. K., Mohagheghpour N., Hansen J. A., Engleman E. G. Alloantigen-specific cytotoxic and suppressor T lymphocytes are derived from phenotypically distinct precursors. J Immunol. 1983 Nov;131(5):2296–2300. [PubMed] [Google Scholar]
  5. Dustin M. L., Olive D., Springer T. A. Correlation of CD2 binding and functional properties of multimeric and monomeric lymphocyte function-associated antigen 3. J Exp Med. 1989 Feb 1;169(2):503–517. doi: 10.1084/jem.169.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dustin M. L., Springer T. A. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature. 1989 Oct 19;341(6243):619–624. doi: 10.1038/341619a0. [DOI] [PubMed] [Google Scholar]
  7. Fraser J. D., Irving B. A., Crabtree G. R., Weiss A. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science. 1991 Jan 18;251(4991):313–316. doi: 10.1126/science.1846244. [DOI] [PubMed] [Google Scholar]
  8. Freedman A. S., Freeman G., Horowitz J. C., Daley J., Nadler L. M. B7, a B-cell-restricted antigen that identifies preactivated B cells. J Immunol. 1987 Nov 15;139(10):3260–3267. [PubMed] [Google Scholar]
  9. Freedman A. S., Munro J. M., Morimoto C., McIntyre B. W., Rhynhart K., Lee N., Nadler L. M. Follicular non-Hodgkin's lymphoma cell adhesion to normal germinal centers and neoplastic follicles involves very late antigen-4 and vascular cell adhesion molecule-1. Blood. 1992 Jan 1;79(1):206–212. [PubMed] [Google Scholar]
  10. Freeman G. J., Freedman A. S., Segil J. M., Lee G., Whitman J. F., Nadler L. M. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714–2722. [PubMed] [Google Scholar]
  11. Geppert T. D., Lipsky P. E. Accessory cell independent proliferation of human T4 cells stimulated by immobilized monoclonal antibodies to CD3. J Immunol. 1987 Mar 15;138(6):1660–1666. [PubMed] [Google Scholar]
  12. Gmünder H., Lesslauer W. A 45-kDa human T-cell membrane glycoprotein functions in the regulation of cell proliferative responses. Eur J Biochem. 1984 Jul 2;142(1):153–160. doi: 10.1111/j.1432-1033.1984.tb08263.x. [DOI] [PubMed] [Google Scholar]
  13. Hara T., Fu S. M., Hansen J. A. Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen). J Exp Med. 1985 Jun 1;161(6):1513–1524. doi: 10.1084/jem.161.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jenkins M. K., Ashwell J. D., Schwartz R. H. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol. 1988 May 15;140(10):3324–3330. [PubMed] [Google Scholar]
  15. June C. H., Ledbetter J. A., Gillespie M. M., Lindsten T., Thompson C. B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol. 1987 Dec;7(12):4472–4481. doi: 10.1128/mcb.7.12.4472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. June C. H., Ledbetter J. A., Lindsten T., Thompson C. B. Evidence for the involvement of three distinct signals in the induction of IL-2 gene expression in human T lymphocytes. J Immunol. 1989 Jul 1;143(1):153–161. [PubMed] [Google Scholar]
  17. Kawakami K., Yamamoto Y., Kakimoto K., Onoue K. Requirement for delivery of signals by physical interaction and soluble factors from accessory cells in the induction of receptor-mediated T cell proliferation. Effectiveness of IFN-gamma modulation of accessory cells for physical interaction with T cells. J Immunol. 1989 Mar 15;142(6):1818–1825. [PubMed] [Google Scholar]
  18. Kohno K., Shibata Y., Matsuo Y., Minowada J. CD28 molecule as a receptor-like function for accessory signals in cell-mediated augmentation of IL-2 production. Cell Immunol. 1990 Nov;131(1):1–10. doi: 10.1016/0008-8749(90)90230-o. [DOI] [PubMed] [Google Scholar]
  19. Ledbetter J. A., Martin P. J., Spooner C. E., Wofsy D., Tsu T. T., Beatty P. G., Gladstone P. Antibodies to Tp67 and Tp44 augment and sustain proliferative responses of activated T cells. J Immunol. 1985 Oct;135(4):2331–2336. [PubMed] [Google Scholar]
  20. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  21. Linsley P. S., Clark E. A., Ledbetter J. A. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5031–5035. doi: 10.1073/pnas.87.13.5031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Manger B., Weiss A., Imboden J., Laing T., Stobo J. D. The role of protein kinase C in transmembrane signaling by the T cell antigen receptor complex. Effects of stimulation with soluble or immobilized CD3 antibodies. J Immunol. 1987 Oct 15;139(8):2755–2760. [PubMed] [Google Scholar]
  23. Marlin S. D., Springer T. A. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell. 1987 Dec 4;51(5):813–819. doi: 10.1016/0092-8674(87)90104-8. [DOI] [PubMed] [Google Scholar]
  24. Martin P. J., Ledbetter J. A., Morishita Y., June C. H., Beatty P. G., Hansen J. A. A 44 kilodalton cell surface homodimer regulates interleukin 2 production by activated human T lymphocytes. J Immunol. 1986 May 1;136(9):3282–3287. [PubMed] [Google Scholar]
  25. Matsuyama T., Yamada A., Kay J., Yamada K. M., Akiyama S. K., Schlossman S. F., Morimoto C. Activation of CD4 cells by fibronectin and anti-CD3 antibody. A synergistic effect mediated by the VLA-5 fibronectin receptor complex. J Exp Med. 1989 Oct 1;170(4):1133–1148. doi: 10.1084/jem.170.4.1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Meuer S. C., Hussey R. E., Fabbi M., Fox D., Acuto O., Fitzgerald K. A., Hodgdon J. C., Protentis J. P., Schlossman S. F., Reinherz E. L. An alternative pathway of T-cell activation: a functional role for the 50 kd T11 sheep erythrocyte receptor protein. Cell. 1984 Apr;36(4):897–906. doi: 10.1016/0092-8674(84)90039-4. [DOI] [PubMed] [Google Scholar]
  27. Mueller D. L., Jenkins M. K., Schwartz R. H. An accessory cell-derived costimulatory signal acts independently of protein kinase C activation to allow T cell proliferation and prevent the induction of unresponsiveness. J Immunol. 1989 Apr 15;142(8):2617–2628. [PubMed] [Google Scholar]
  28. Ramsdell F., Fowlkes B. J. Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science. 1990 Jun 15;248(4961):1342–1348. doi: 10.1126/science.1972593. [DOI] [PubMed] [Google Scholar]
  29. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  30. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  31. Streuli M., Saito H. Regulation of tissue-specific alternative splicing: exon-specific cis-elements govern the splicing of leukocyte common antigen pre-mRNA. EMBO J. 1989 Mar;8(3):787–796. doi: 10.1002/j.1460-2075.1989.tb03439.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Thompson C. B., Lindsten T., Ledbetter J. A., Kunkel S. L., Young H. A., Emerson S. G., Leiden J. M., June C. H. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333–1337. doi: 10.1073/pnas.86.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Turka L. A., Ledbetter J. A., Lee K., June C. H., Thompson C. B. CD28 is an inducible T cell surface antigen that transduces a proliferative signal in CD3+ mature thymocytes. J Immunol. 1990 Mar 1;144(5):1646–1653. [PubMed] [Google Scholar]
  34. Van Seventer G. A., Shimizu Y., Horgan K. J., Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990 Jun 15;144(12):4579–4586. [PubMed] [Google Scholar]
  35. Van Wauwe J. P., De Mey J. R., Goossens J. G. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol. 1980 Jun;124(6):2708–2713. [PubMed] [Google Scholar]
  36. Weaver C. T., Unanue E. R. The costimulatory function of antigen-presenting cells. Immunol Today. 1990 Feb;11(2):49–55. doi: 10.1016/0167-5699(90)90018-5. [DOI] [PubMed] [Google Scholar]
  37. Weiss A., Manger B., Imboden J. Synergy between the T3/antigen receptor complex and Tp44 in the activation of human T cells. J Immunol. 1986 Aug 1;137(3):819–825. [PubMed] [Google Scholar]
  38. Williams I. R., Unanue E. R. Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody. J Immunol. 1990 Jul 1;145(1):85–93. [PubMed] [Google Scholar]
  39. Wiskocil R., Weiss A., Imboden J., Kamin-Lewis R., Stobo J. Activation of a human T cell line: a two-stimulus requirement in the pretranslational events involved in the coordinate expression of interleukin 2 and gamma-interferon genes. J Immunol. 1985 Mar;134(3):1599–1603. [PubMed] [Google Scholar]
  40. Yamada H., Martin P. J., Bean M. A., Braun M. P., Beatty P. G., Sadamoto K., Hansen J. A. Monoclonal antibody 9.3 and anti-CD11 antibodies define reciprocal subsets of lymphocytes. Eur J Immunol. 1985 Dec;15(12):1164–1168. doi: 10.1002/eji.1830151204. [DOI] [PubMed] [Google Scholar]
  41. van Noesel C., Miedema F., Brouwer M., de Rie M. A., Aarden L. A., van Lier R. A. Regulatory properties of LFA-1 alpha and beta chains in human T-lymphocyte activation. Nature. 1988 Jun 30;333(6176):850–852. doi: 10.1038/333850a0. [DOI] [PubMed] [Google Scholar]

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