Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Apr 1;177(4):925–935. doi: 10.1084/jem.177.4.925

Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal

PMCID: PMC2190967  PMID: 7681471

Abstract

Cognate interactions between antigen-presenting B and T cells play crucial roles in immunologic responses. T cells that have been activated via the crosslinking of CD3 are able to induce B cell proliferation and immunoglobulin secretion in a major histocompatibility complex-unrestricted and contact-dependent manner. We find that such activated human CD4+ T cells, but not control Ig- treated T cells, may induce normal or leukemic B cells to express B7/BB1 and significantly higher levels of CD54 intercellular adhesion molecule 1 via a process that also requires direct cell-cell contact. To discern what cell surface molecule(s) may be responsible for signalling B cells to express B7/BB1, we added various monoclonal antibodies (mAbs) specific for T or B cell accessory molecules or control mAbs to cocultures of alpha-CD3-activated T cells and resting B cells. We find that only alpha-CD40 mAbs can significantly inhibit the increased expression of B7/BB1, suggesting that the ligand for CD40 expressed on activated T cells may be an important inducer of B7/BB1 expression. Subsequent experiments in fact demonstrate that alpha-CD40 mAbs, but not control mAbs, induce changes in B cell phenotype similar to those induced by activated T cells when the mAbs are presented on Fc gamma RII (CDw32)-expressing L cells. These phenotypic changes have significant effects on B cell function. Whereas chronic lymphocytic leukemia (CLL) B cells normally are very poor stimulators in allogeneic mixed lymphocyte reactions (MLRs), CLL-B cells preactivated via CD40 crosslinking are significantly better presenters of alloantigen, affecting up to 30-fold-greater stimulation of T cell proliferation than that induced by control treated or nontreated CLL-B cells. Similarly, the MLR of T cells stimulated by allogeneic nonleukemic B cells can be enhanced significantly if the stimulator B cells are preactivated via CD40 crosslinking. The enhanced MLR generated by such preactivated B cells may be inhibited by blocking B7/BB1-CD28 interaction with CTLA4Ig. These studies demonstrate a novel, CD40- dependent pathway for inducing B cell expression of B7/BB1 and enhancing B cell antigen-presenting cell activity that can be initiated via cell-cell contact with alpha-CD3-stimulated CD4+ T cells.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Abbas A. K., Haber S., Rock K. L. Antigen presentation by hapten-specific B lymphocytes. II. Specificity and properties of antigen-presenting B lymphocytes, and function of immunoglobulin receptors. J Immunol. 1985 Sep;135(3):1661–1667. [PubMed] [Google Scholar]
  2. Azuma M., Cayabyab M., Buck D., Phillips J. H., Lanier L. L. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J Exp Med. 1992 Feb 1;175(2):353–360. doi: 10.1084/jem.175.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baldini L., Cro L., Calori R., Nobili L., Silvestris I., Maiolo A. T. Differential expression of very late activation antigen-3 (VLA-3)/VLA-4 in B-cell non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia. Blood. 1992 May 15;79(10):2688–2693. [PubMed] [Google Scholar]
  4. Barrett T. B., Shu G., Clark E. A. CD40 signaling activates CD11a/CD18 (LFA-1)-mediated adhesion in B cells. J Immunol. 1991 Mar 15;146(6):1722–1729. [PubMed] [Google Scholar]
  5. Clark E. A., Ledbetter J. A. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4494–4498. doi: 10.1073/pnas.83.12.4494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clark E. A., Shu G. L., Lüscher B., Draves K. E., Banchereau J., Ledbetter J. A., Valentine M. A. Activation of human B cells. Comparison of the signal transduced by IL-4 to four different competence signals. J Immunol. 1989 Dec 15;143(12):3873–3880. [PubMed] [Google Scholar]
  7. Damle N. K., Klussman K., Linsley P. S., Aruffo A. Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J Immunol. 1992 Apr 1;148(7):1985–1992. [PubMed] [Google Scholar]
  8. Eynon E. E., Parker D. C. Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med. 1992 Jan 1;175(1):131–138. doi: 10.1084/jem.175.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Foon K. A., Rai K. R., Gale R. P. Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Intern Med. 1990 Oct 1;113(7):525–539. doi: 10.7326/0003-4819-113-7-525. [DOI] [PubMed] [Google Scholar]
  10. Freedman A. S., Boyd A. W., Bieber F. R., Daley J., Rosen K., Horowitz J. C., Levy D. N., Nadler L. M. Normal cellular counterparts of B cell chronic lymphocytic leukemia. Blood. 1987 Aug;70(2):418–427. [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Freudenthal P. S., Steinman R. M. The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7698–7702. doi: 10.1073/pnas.87.19.7698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Frohman M., Cowing C. Presentation of antigen by B cells: functional dependence on radiation dose, interleukins, cellular activation, and differential glycosylation. J Immunol. 1985 Apr;134(4):2269–2275. [PubMed] [Google Scholar]
  15. Galy A. H., Spits H. CD40 is functionally expressed on human thymic epithelial cells. J Immunol. 1992 Aug 1;149(3):775–782. [PubMed] [Google Scholar]
  16. Geppert T. D., Lipsky P. E. Immobilized anti-CD3-induced T cell growth: comparison of the frequency of responding cells within various T cell subsets. Cell Immunol. 1991 Mar;133(1):206–218. doi: 10.1016/0008-8749(91)90192-e. [DOI] [PubMed] [Google Scholar]
  17. Han T., Bloom M. L., Dadey B., Bennett G., Minowada J., Sandberg A. A., Ozer H. Lack of autologous mixed lymphocyte reaction in patients with chronic lymphocytic leukemia: evidence for autoreactive T-cell dysfunction not correlated with phenotype, karyotype, or clinical status. Blood. 1982 Nov;60(5):1075–1081. [PubMed] [Google Scholar]
  18. Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
  19. Hirohata S., Jelinek D. F., Lipsky P. E. T cell-dependent activation of B cell proliferation and differentiation by immobilized monoclonal antibodies to CD3. J Immunol. 1988 Jun 1;140(11):3736–3744. [PubMed] [Google Scholar]
  20. Hodgkin P. D., Yamashita L. C., Coffman R. L., Kehry M. R. Separation of events mediating B cell proliferation and Ig production by using T cell membranes and lymphokines. J Immunol. 1990 Oct 1;145(7):2025–2034. [PubMed] [Google Scholar]
  21. Inaba K., Steinman R. M. Protein-specific helper T-lymphocyte formation initiated by dendritic cells. Science. 1985 Aug 2;229(4712):475–479. doi: 10.1126/science.3160115. [DOI] [PubMed] [Google Scholar]
  22. Inaba K., Steinman R. M. Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release. J Exp Med. 1984 Dec 1;160(6):1717–1735. doi: 10.1084/jem.160.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Inghirami G., Wieczorek R., Zhu B. Y., Silber R., Dalla-Favera R., Knowles D. M. Differential expression of LFA-1 molecules in non-Hodgkin's lymphoma and lymphoid leukemia. Blood. 1988 Oct;72(4):1431–1434. [PubMed] [Google Scholar]
  24. Janeway C. A., Jr, Ron J., Katz M. E. The B cell is the initiating antigen-presenting cell in peripheral lymph nodes. J Immunol. 1987 Feb 15;138(4):1051–1055. [PubMed] [Google Scholar]
  25. June C. H., Fletcher M. C., Ledbetter J. A., Schieven G. L., Siegel J. N., Phillips A. F., Samelson L. E. Inhibition of tyrosine phosphorylation prevents T-cell receptor-mediated signal transduction. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7722–7726. doi: 10.1073/pnas.87.19.7722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kay N. E., Perri R. T. Immunobiology of malignant B cells and immunoregulatory cells in B-chronic lymphocytic leukemia. Clin Lab Med. 1988 Mar;8(1):163–177. [PubMed] [Google Scholar]
  27. Kipps T. J., Meisenholder G., Robbins B. A. New developments in flow cytometric analyses of lymphocyte markers. Clin Lab Med. 1992 Jun;12(2):237–275. [PubMed] [Google Scholar]
  28. Kipps T. J. The CD5 B cell. Adv Immunol. 1989;47:117–185. doi: 10.1016/s0065-2776(08)60663-x. [DOI] [PubMed] [Google Scholar]
  29. Ko H. S., Fu S. M., Winchester R. J., Yu D. T., Kunkel H. G. Ia determinants on stimulated human T lymphocytes. Occurrence on mitogen- and antigen-activated T cells. J Exp Med. 1979 Aug 1;150(2):246–255. doi: 10.1084/jem.150.2.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Koulova L., Clark E. A., Shu G., Dupont B. The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells. J Exp Med. 1991 Mar 1;173(3):759–762. doi: 10.1084/jem.173.3.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kurt-Jones E. A., Liano D., HayGlass K. A., Benacerraf B., Sy M. S., Abbas A. K. The role of antigen-presenting B cells in T cell priming in vivo. Studies of B cell-deficient mice. J Immunol. 1988 Jun 1;140(11):3773–3778. [PubMed] [Google Scholar]
  32. Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985 Apr 11;314(6011):537–539. doi: 10.1038/314537a0. [DOI] [PubMed] [Google Scholar]
  33. Lin R. H., Mamula M. J., Hardin J. A., Janeway C. A., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. doi: 10.1084/jem.173.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Linsley P. S., Brady W., Urnes M., Grosmaire L. S., Damle N. K., Ledbetter J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561–569. doi: 10.1084/jem.174.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Linsley P. S., Wallace P. M., Johnson J., Gibson M. G., Greene J. L., Ledbetter J. A., Singh C., Tepper M. A. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992 Aug 7;257(5071):792–795. doi: 10.1126/science.1496399. [DOI] [PubMed] [Google Scholar]
  37. Mamula M. J., Lin R. H., Janeway C. A., Jr, Hardin J. A. Breaking T cell tolerance with foreign and self co-immunogens. A study of autoimmune B and T cell epitopes of cytochrome c. J Immunol. 1992 Aug 1;149(3):789–795. [PubMed] [Google Scholar]
  38. Metlay J. P., Puré E., Steinman R. M. Distinct features of dendritic cells and anti-Ig activated B cells as stimulators of the primary mixed leukocyte reaction. J Exp Med. 1989 Jan 1;169(1):239–254. doi: 10.1084/jem.169.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mustelin T., Coggeshall K. M., Isakov N., Altman A. T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation. Science. 1990 Mar 30;247(4950):1584–1587. doi: 10.1126/science.2138816. [DOI] [PubMed] [Google Scholar]
  40. Noelle R. J., Daum J., Bartlett W. C., McCann J., Shepherd D. M. Cognate interactions between helper T cells and B cells. V. Reconstitution of T helper cell function using purified plasma membranes from activated Th1 and Th2 T helper cells and lymphokines. J Immunol. 1991 Feb 15;146(4):1118–1124. [PubMed] [Google Scholar]
  41. Noelle R. J., McCann J., Marshall L., Bartlett W. C. Cognate interactions between helper T cells and B cells. III. Contact-dependent, lymphokine-independent induction of B cell cycle entry by activated helper T cells. J Immunol. 1989 Sep 15;143(6):1807–1814. [PubMed] [Google Scholar]
  42. Noelle R. J., Roy M., Shepherd D. M., Stamenkovic I., Ledbetter J. A., Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550–6554. doi: 10.1073/pnas.89.14.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Oshima S., Eckels D. D. Selective signal transduction through the CD3 or CD2 complex is required for class II MHC expression by human T cells. J Immunol. 1990 Dec 15;145(12):4018–4025. [PubMed] [Google Scholar]
  44. Ron Y., Sprent J. T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes. J Immunol. 1987 May 1;138(9):2848–2856. [PubMed] [Google Scholar]
  45. Rousset F., Garcia E., Banchereau J. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J Exp Med. 1991 Mar 1;173(3):705–710. doi: 10.1084/jem.173.3.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sanders V. M., Snyder J. M., Uhr J. W., Vitetta E. S. Characterization of the physical interaction between antigen-specific B and T cells. J Immunol. 1986 Oct 15;137(8):2395–2404. [PubMed] [Google Scholar]
  47. Sanders V. M., Vitetta E. S. B cell-associated LFA-1 and T cell-associated ICAM-1 transiently cluster in the area of contact between interacting cells. Cell Immunol. 1991 Jan;132(1):45–55. doi: 10.1016/0008-8749(91)90005-v. [DOI] [PubMed] [Google Scholar]
  48. 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]
  49. Seki N., Sudo Y., Yoshioka T., Sugihara S., Fujitsu T., Sakuma S., Ogawa T., Hamaoka T., Senoh H., Fujiwara H. Type II collagen-induced murine arthritis. I. Induction and perpetuation of arthritis require synergy between humoral and cell-mediated immunity. J Immunol. 1988 Mar 1;140(5):1477–1484. [PubMed] [Google Scholar]
  50. 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]
  51. Stohl W., Posnett D. N., Chiorazzi N. Induction of T cell-dependent B cell differentiation by anti-CD3 monoclonal antibodies. J Immunol. 1987 Mar 15;138(6):1667–1673. [PubMed] [Google Scholar]
  52. Taurog J. D., Kerwar S. S., McReynolds R. A., Sandberg G. P., Leary S. L., Mahowald M. L. Synergy between adjuvant arthritis and collagen-induced arthritis in rats. J Exp Med. 1985 Sep 1;162(3):962–978. doi: 10.1084/jem.162.3.962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tohma S., Lipsky P. E. Analysis of the mechanisms of T cell-dependent polyclonal activation of human B cells. Induction of human B cell responses by fixed activated T cells. J Immunol. 1991 Apr 15;146(8):2544–2552. [PubMed] [Google Scholar]
  54. Vernino L., McAnally L. M., Ramberg J., Lipsky P. E. Generation of nondividing high rate Ig-secreting plasma cells in cultures of human B cells stimulated with anti-CD3-activated T cells. J Immunol. 1992 Jan 15;148(2):404–410. [PubMed] [Google Scholar]
  55. Whalen B. J., Tony H. P., Parker D. C. Characterization of the effector mechanism of help for antigen-presenting and bystander resting B cell growth mediated by Ia-restricted Th2 helper T cell lines. J Immunol. 1988 Oct 1;141(7):2230–2239. [PubMed] [Google Scholar]
  56. Wolos J. A., Davey F. R. Depressed stimulation in the MLR by B lymphocytes on chronic lymphocytic leukemia: failure to demonstrate a suppressor cell. Clin Immunol Immunopathol. 1979 Sep;14(1):77–85. doi: 10.1016/0090-1229(79)90128-4. [DOI] [PubMed] [Google Scholar]
  57. Young J. W., Koulova L., Soergel S. A., Clark E. A., Steinman R. M., Dupont B. The B7/BB1 antigen provides one of several costimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro. J Clin Invest. 1992 Jul;90(1):229–237. doi: 10.1172/JCI115840. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES