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. 1994 Apr 1;179(4):1205–1214. doi: 10.1084/jem.179.4.1205

T cell costimulation by B7/BB1 induces CD8 T cell-dependent tumor rejection: an important role of B7/BB1 in the induction, recruitment, and effector function of antitumor T cells

PMCID: PMC2191463  PMID: 7511683

Abstract

A successful antitumor T cell immune response involves induction, recruitment, and effector function of T cells. While B7/BB1 is known as a major costimulatory molecule in the induction of T cell responses, its role in T cell recruitment and effector function is still unclear. In this study, we show that introducing a major costimulatory molecule B7/BB1 into a major histocompatibility complex class II-negative tumor cell line, J558, results in a drastic reduction of its tumorigenicity. The tumor rejection depends on CD8 T cells but not CD4 T cells. However, unlike the previous reports on melanoma cell lines, B7/BB1- transfected J558 cells fail to induce cross-protection against parental J558 cells. The B7/BB1-transfected (J558-B7), but not untransfected J558 cells (J558-Neo) induce a CD8 T cell-dominant inflammatory response, and the T cells isolated from the tumor infiltrating lymphocytes (TIL) are polyclonal in terms of their T cell receptor V beta usage. Most surprisingly, the freshly prepared TIL have a potent, CD8 T cell-mediated cytotoxicity on tumor cells without any in vitro stimulation. The cytotoxic T lymphocyte (CTL) activity can be blocked by anti-CD8 monoclonal antibody (mAb). Interestingly, the CTL lyse J558- B7 about 10- to 80-fold more efficiently than untransfected J558-Neo cells. This preferential lysis cannot be attributed to recognition of B7/BB1-derived antigen by the T cells. This finding, together with the lack of the cross-protection between the J558-B7 and J558-Neo, suggests that B7/BB1 can also function at the effector phase of CTL responses. This notion is confirmed by our findings that the lysis of J558-B7 can be blocked by anti-B7 mAbs. Taken together, our results indicate that not only can the B7/BB1 molecule function as a costimulatory molecule at the initiation of immune response, it can also play a major role in T cell recruitment and effector function. This conclusion has significant implications for immunotherapy of tumors.

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Selected References

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  1. Allan J. E., Dixon J. E., Doherty P. C. Nature of the inflammatory process in the central nervous system of mice infected with lymphocytic choriomeningitis virus. Curr Top Microbiol Immunol. 1987;134:131–143. doi: 10.1007/978-3-642-71726-0_6. [DOI] [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. Azuma M., Cayabyab M., Phillips J. H., Lanier L. L. Requirements for CD28-dependent T cell-mediated cytotoxicity. J Immunol. 1993 Mar 15;150(6):2091–2101. [PubMed] [Google Scholar]
  4. Bill J., Kanagawa O., Woodland D. L., Palmer E. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells. J Exp Med. 1989 Apr 1;169(4):1405–1419. doi: 10.1084/jem.169.4.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ceredig R., Allan J. E., Tabi Z., Lynch F., Doherty P. C. Phenotypic analysis of the inflammatory exudate in murine lymphocytic choriomeningitis. J Exp Med. 1987 Jun 1;165(6):1539–1551. doi: 10.1084/jem.165.6.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen L., Ashe S., Brady W. A., Hellström I., Hellström K. E., Ledbetter J. A., McGowan P., Linsley P. S. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093–1102. doi: 10.1016/s0092-8674(05)80059-5. [DOI] [PubMed] [Google Scholar]
  7. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
  8. Dumont F. J., Habbersett R. C., Coker L. Z., Nichols E. A., Treffinger J. A. High level expression of the plasma cell antigen PC.1 on the T-cell subset expanding in MRL/MpJ-lpr/lpr mice: detection with a xenogeneic monoclonal antibody and alloantisera. Cell Immunol. 1985 Dec;96(2):327–337. doi: 10.1016/0008-8749(85)90364-8. [DOI] [PubMed] [Google Scholar]
  9. Gao E. K., Kanagawa O., Sprent J. Capacity of unprimed CD4+ and CD8+ T cells expressing V beta 11 receptors to respond to I-E alloantigens in vivo. J Exp Med. 1989 Dec 1;170(6):1947–1957. doi: 10.1084/jem.170.6.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Greenberg P. D. Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol. 1991;49:281–355. doi: 10.1016/s0065-2776(08)60778-6. [DOI] [PubMed] [Google Scholar]
  11. Harding F. A., Allison J. P. CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help. J Exp Med. 1993 Jun 1;177(6):1791–1796. doi: 10.1084/jem.177.6.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Janeway C. A., Jr The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today. 1992 Jan;13(1):11–16. doi: 10.1016/0167-5699(92)90198-G. [DOI] [PubMed] [Google Scholar]
  14. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jenkins M. K., Taylor P. S., Norton S. D., Urdahl K. B. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991 Oct 15;147(8):2461–2466. [PubMed] [Google Scholar]
  16. June C. H., Ledbetter J. A., Linsley P. S., Thompson C. B. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990 Jun;11(6):211–216. doi: 10.1016/0167-5699(90)90085-n. [DOI] [PubMed] [Google Scholar]
  17. Kanagawa O., Palmer E., Bill J. The T cell receptor V beta 6 domain imparts reactivity to the Mls-1a antigen. Cell Immunol. 1989 Apr 1;119(2):412–426. doi: 10.1016/0008-8749(89)90255-4. [DOI] [PubMed] [Google Scholar]
  18. Kappler J. W., Skidmore B., White J., Marrack P. Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition. J Exp Med. 1981 May 1;153(5):1198–1214. doi: 10.1084/jem.153.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Lafferty K. J., Prowse S. J., Simeonovic C. J., Warren H. S. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol. 1983;1:143–173. doi: 10.1146/annurev.iy.01.040183.001043. [DOI] [PubMed] [Google Scholar]
  21. Ledbetter J. A., Rouse R. V., Micklem H. S., Herzenberg L. A. T cell subsets defined by expression of Lyt-1,2,3 and Thy-1 antigens. Two-parameter immunofluorescence and cytotoxicity analysis with monoclonal antibodies modifies current views. J Exp Med. 1980 Aug 1;152(2):280–295. doi: 10.1084/jem.152.2.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lenschow D. J., Zeng Y., Thistlethwaite J. R., Montag A., Brady W., Gibson M. G., Linsley P. S., Bluestone J. A. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992 Aug 7;257(5071):789–792. doi: 10.1126/science.1323143. [DOI] [PubMed] [Google Scholar]
  23. Liao N. S., Maltzman J., Raulet D. H. Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells. J Exp Med. 1989 Jul 1;170(1):135–143. doi: 10.1084/jem.170.1.135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Liu Y., Blanden R. V., Müllbacher A. Identification of cytolytic lymphocytes in West Nile virus-infected murine central nervous system. J Gen Virol. 1989 Mar;70(Pt 3):565–573. doi: 10.1099/0022-1317-70-3-565. [DOI] [PubMed] [Google Scholar]
  27. Liu Y., Janeway C. A., Jr Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance. J Exp Med. 1990 Dec 1;172(6):1735–1739. doi: 10.1084/jem.172.6.1735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Liu Y., Jones B., Brady W., Janeway C. A., Jr, Linsley P. S., Linley P. S. Co-stimulation of murine CD4 T cell growth: cooperation between B7 and heat-stable antigen. Eur J Immunol. 1992 Nov;22(11):2855–2859. doi: 10.1002/eji.1830221115. [DOI] [PubMed] [Google Scholar]
  29. Liu Y., Linsley P. S. Costimulation of T-cell growth. Curr Opin Immunol. 1992 Jun;4(3):265–270. doi: 10.1016/0952-7915(92)90075-p. [DOI] [PubMed] [Google Scholar]
  30. Okada C. Y., Holzmann B., Guidos C., Palmer E., Weissman I. L. Characterization of a rat monoclonal antibody specific for a determinant encoded by the V beta 7 gene segment. Depletion of V beta 7+ T cells in mice with Mls-1a haplotype. J Immunol. 1990 May 1;144(9):3473–3477. [PubMed] [Google Scholar]
  31. Ozato K., Wan Y. J., Orrison B. M. Mouse major histocompatibility class I gene expression begins at midsomite stage and is inducible in earlier-stage embryos by interferon. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2427–2431. doi: 10.1073/pnas.82.8.2427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pullen A. M., Marrack P., Kappler J. W. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature. 1988 Oct 27;335(6193):796–801. doi: 10.1038/335796a0. [DOI] [PubMed] [Google Scholar]
  33. Razi-Wolf Z., Freeman G. J., Galvin F., Benacerraf B., Nadler L., Reiser H. Expression and function of the murine B7 antigen, the major costimulatory molecule expressed by peritoneal exudate cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4210–4214. doi: 10.1073/pnas.89.9.4210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Razi-Wolf Z., Freeman G. J., Galvin F., Benacerraf B., Nadler L., Reiser H. Expression and function of the murine B7 antigen, the major costimulatory molecule expressed by peritoneal exudate cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4210–4214. doi: 10.1073/pnas.89.9.4210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Restifo N. P., Esquivel F., Asher A. L., Stötter H., Barth R. J., Bennink J. R., Mulé J. J., Yewdell J. W., Rosenberg S. A. Defective presentation of endogenous antigens by a murine sarcoma. Implications for the failure of an anti-tumor immune response. J Immunol. 1991 Aug 15;147(4):1453–1459. [PMC free article] [PubMed] [Google Scholar]
  36. Restifo N. P., Spiess P. J., Karp S. E., Mulé J. J., Rosenberg S. A. A nonimmunogenic sarcoma transduced with the cDNA for interferon gamma elicits CD8+ T cells against the wild-type tumor: correlation with antigen presentation capability. J Exp Med. 1992 Jun 1;175(6):1423–1431. doi: 10.1084/jem.175.6.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sanchez-Madrid F., Simon P., Thompson S., Springer T. A. Mapping of antigenic and functional epitopes on the alpha- and beta-subunits of two related mouse glycoproteins involved in cell interactions, LFA-1 and Mac-1. J Exp Med. 1983 Aug 1;158(2):586–602. doi: 10.1084/jem.158.2.586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  39. Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
  40. Talmage D. W., Woolnough J. A., Hemmingsen H., Lopez L., Lafferty K. J. Activation of cytotoxic T cells by nonstimulating tumor cells and spleen cell factor(s). Proc Natl Acad Sci U S A. 1977 Oct;74(10):4610–4614. doi: 10.1073/pnas.74.10.4610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tan P., Anasetti C., Hansen J. A., Melrose J., Brunvand M., Bradshaw J., Ledbetter J. A., Linsley P. S. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med. 1993 Jan 1;177(1):165–173. doi: 10.1084/jem.177.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Townsend S. E., Allison J. P. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science. 1993 Jan 15;259(5093):368–370. doi: 10.1126/science.7678351. [DOI] [PubMed] [Google Scholar]
  43. Turka L. A., Linsley P. S., Lin H., Brady W., Leiden J. M., Wei R. Q., Gibson M. L., Zheng X. G., Myrdal S., Gordon D. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11102–11105. doi: 10.1073/pnas.89.22.11102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wu Y., Guo Y., Liu Y. A major costimulatory molecule on antigen-presenting cells, CTLA4 ligand A, is distinct from B7. J Exp Med. 1993 Nov 1;178(5):1789–1793. doi: 10.1084/jem.178.5.1789. [DOI] [PMC free article] [PubMed] [Google Scholar]

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