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. 1993 Jun;67(6):3134–3141. doi: 10.1128/jvi.67.6.3134-3141.1993

The mitogenic activity of human T-cell leukemia virus type I is T-cell associated and requires the CD2/LFA-3 activation pathway.

J T Kimata 1, T J Palker 1, L Ratner 1
PMCID: PMC237651  PMID: 7684460

Abstract

The presence of a high number of activated T cells in the bloodstream and spontaneous proliferation of peripheral blood mononuclear cells in vitro are striking characteristics of human T-cell leukemia virus type I (HTLV-I) infection. The HTLV-I regulatory protein Tax and the envelope protein gp46 have been implicated in mediating the activation process. In this study, HTLV-I-producing cell lines and purified virus from the cell lines were examined for the ability to activate peripheral blood lymphocytes (PBLs) and Jurkat cells. Antisera and monoclonal antibodies against several cellular adhesion proteins involved in T-cell activation and against viral proteins were used to identify which molecules may be participating in the activation process. First, neither virus from a T-cell line, MT2, nor virus produced from the human osteosarcoma cell line HOS/PL was able to induce PBLs to proliferate. In contrast, both fixed and irradiated HTLV-I-producing T-cell lines induced proliferation of PBLs; HOS/PL cells did not activate PBLs. Second, HTLV-I-positive T-cell lines were capable of activating interleukin-2 mRNA expression in Jurkat cells. Induction of interleukin-2 expression was inhibited by anti-CD2 and anti-lymphocyte function-associated antigen 3 (LFA-3) monoclonal antibodies but not anti-human leukocyte antigen-DR, anti-CD4, anti-LFA-1, or anti-intercellular adhesion molecule 1. Similar results were obtained with PBLs as the responder cells. Furthermore, monoclonal antibodies and antisera against various regions of the HTLV-I envelope proteins gp46 and gp21 as well as p40tax did not block activation. These data indicate that HTLV-I viral particles are not intrinsically mitogenic and that infection of target T cells is not necessary for activation. Instead, the mitogenic activity is restricted to virus-producing T cells, requires cell-to-cell contact, and may be mediated through the LFA-3/CD2 activation pathway.

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Selected References

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

  1. Berneman Z. N., Gartenhaus R. B., Reitz M. S., Jr, Blattner W. A., Manns A., Hanchard B., Ikehara O., Gallo R. C., Klotman M. E. Expression of alternatively spliced human T-lymphotropic virus type I pX mRNA in infected cell lines and in primary uncultured cells from patients with adult T-cell leukemia/lymphoma and healthy carriers. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3005–3009. doi: 10.1073/pnas.89.7.3005. [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. Bockenstedt L. K., Goldsmith M. A., Dustin M., Olive D., Springer T. A., Weiss A. The CD2 ligand LFA-3 activates T cells but depends on the expression and function of the antigen receptor. J Immunol. 1988 Sep 15;141(6):1904–1911. [PubMed] [Google Scholar]
  4. Brod S. A., Purvee M., Benjamin D., Hafler D. A. T-T cell interactions are mediated by adhesion molecules. Eur J Immunol. 1990 Oct;20(10):2259–2268. doi: 10.1002/eji.1830201015. [DOI] [PubMed] [Google Scholar]
  5. Chelly J., Kaplan J. C., Maire P., Gautron S., Kahn A. Transcription of the dystrophin gene in human muscle and non-muscle tissue. Nature. 1988 Jun 30;333(6176):858–860. doi: 10.1038/333858a0. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Ciminale V., Pavlakis G. N., Derse D., Cunningham C. P., Felber B. K. Complex splicing in the human T-cell leukemia virus (HTLV) family of retroviruses: novel mRNAs and proteins produced by HTLV type I. J Virol. 1992 Mar;66(3):1737–1745. doi: 10.1128/jvi.66.3.1737-1745.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clapham P., Nagy K., Cheingsong-Popov R., Exley M., Weiss R. A. Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. Science. 1983 Dec 9;222(4628):1125–1127. doi: 10.1126/science.6316502. [DOI] [PubMed] [Google Scholar]
  9. Crabtree G. R. Contingent genetic regulatory events in T lymphocyte activation. Science. 1989 Jan 20;243(4889):355–361. doi: 10.1126/science.2783497. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Dodon M. D., Bernard A., Gazzolo L. Peripheral T-lymphocyte activation by human T-cell leukemia virus type I interferes with the CD2 but not with the CD3/TCR pathway. J Virol. 1989 Dec;63(12):5413–5419. doi: 10.1128/jvi.63.12.5413-5419.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Duyao M. P., Kessler D. J., Spicer D. B., Bartholomew C., Cleveland J. L., Siekevitz M., Sonenshein G. E. Transactivation of the c-myc promoter by human T cell leukemia virus type 1 tax is mediated by NF kappa B. J Biol Chem. 1992 Aug 15;267(23):16288–16291. [PubMed] [Google Scholar]
  14. Fujii M., Sassone-Corsi P., Verma I. M. c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8526–8530. doi: 10.1073/pnas.85.22.8526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gazzolo L., Duc Dodon M. Direct activation of resting T lymphocytes by human T-lymphotropic virus type I. Nature. 1987 Apr 16;326(6114):714–717. doi: 10.1038/326714a0. [DOI] [PubMed] [Google Scholar]
  16. Gessain A., Louie A., Gout O., Gallo R. C., Franchini G. Human T-cell leukemia-lymphoma virus type I (HTLV-I) expression in fresh peripheral blood mononuclear cells from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy. J Virol. 1991 Mar;65(3):1628–1633. doi: 10.1128/jvi.65.3.1628-1633.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gootenberg J. E., Ruscetti F. W., Mier J. W., Gazdar A., Gallo R. C. Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor. J Exp Med. 1981 Nov 1;154(5):1403–1418. doi: 10.1084/jem.154.5.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hünig T., Tiefenthaler G., Meyer zum Büschenfelde K. H., Meuer S. C. Alternative pathway activation of T cells by binding of CD2 to its cell-surface ligand. Nature. 1987 Mar 19;326(6110):298–301. doi: 10.1038/326298a0. [DOI] [PubMed] [Google Scholar]
  19. Itoyama Y., Minato S., Kira J., Goto I., Sato H., Okochi K., Yamamoto N. Spontaneous proliferation of peripheral blood lymphocytes increased in patients with HTLV-I-associated myelopathy. Neurology. 1988 Aug;38(8):1302–1307. doi: 10.1212/wnl.38.8.1302. [DOI] [PubMed] [Google Scholar]
  20. Jacobson S., Zaninovic V., Mora C., Rodgers-Johnson P., Sheremata W. A., Gibbs C. J., Jr, Gajdusek C., McFarlin D. E. Immunological findings in neurological diseases associated with antibodies to HTLV-I: activated lymphocytes in tropical spastic paraparesis. Ann Neurol. 1988;23 (Suppl):S196–S200. doi: 10.1002/ana.410230744. [DOI] [PubMed] [Google Scholar]
  21. Kelly K., Davis P., Mitsuya H., Irving S., Wright J., Grassmann R., Fleckenstein B., Wano Y., Greene W., Siebenlist U. A high proportion of early response genes are constitutively activated in T cells by HTLV-I. Oncogene. 1992 Aug;7(8):1463–1470. [PubMed] [Google Scholar]
  22. Kimata J. T., Ratner L. Temporal regulation of viral and cellular gene expression during human T-lymphotropic virus type I-mediated lymphocyte immortalization. J Virol. 1991 Aug;65(8):4398–4407. doi: 10.1128/jvi.65.8.4398-4407.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koralnik I. J., Gessain A., Klotman M. E., Lo Monico A., Berneman Z. N., Franchini G. Protein isoforms encoded by the pX region of human T-cell leukemia/lymphotropic virus type I. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8813–8817. doi: 10.1073/pnas.89.18.8813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Marriott S. J., Lindholm P. F., Reid R. L., Brady J. N. Soluble HTLV-I Tax1 protein stimulates proliferation of human peripheral blood lymphocytes. New Biol. 1991 Jul;3(7):678–686. [PubMed] [Google Scholar]
  25. Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
  26. Matsushita S., Robert-Guroff M., Trepel J., Cossman J., Mitsuya H., Broder S. Human monoclonal antibody directed against an envelope glycoprotein of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2672–2676. doi: 10.1073/pnas.83.8.2672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Palker T. J., Riggs E. R., Spragion D. E., Muir A. J., Scearce R. M., Randall R. R., McAdams M. W., McKnight A., Clapham P. R., Weiss R. A. Mapping of homologous, amino-terminal neutralizing regions of human T-cell lymphotropic virus type I and II gp46 envelope glycoproteins. J Virol. 1992 Oct;66(10):5879–5889. doi: 10.1128/jvi.66.10.5879-5889.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Palker T. J., Tanner M. E., Scearce R. M., Streilein R. D., Clark M. E., Haynes B. F. Mapping of immunogenic regions of human T cell leukemia virus type I (HTLV-I) gp46 and gp21 envelope glycoproteins with env-encoded synthetic peptides and a monoclonal antibody to gp46. J Immunol. 1989 Feb 1;142(3):971–978. [PubMed] [Google Scholar]
  30. Ratner L., Vander Heyden N., Garcia J., Polinsky M., Westervelt P., Becich M. Formation of noninfectious HIV-1 virus particles lacking a full-length envelope protein. AIDS Res Hum Retroviruses. 1991 Mar;7(3):287–294. doi: 10.1089/aid.1991.7.287. [DOI] [PubMed] [Google Scholar]
  31. Richardson J. H., Edwards A. J., Cruickshank J. K., Rudge P., Dalgleish A. G. In vivo cellular tropism of human T-cell leukemia virus type 1. J Virol. 1990 Nov;64(11):5682–5687. doi: 10.1128/jvi.64.11.5682-5687.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sanchez-Madrid F., Krensky A. M., Ware C. F., Robbins E., Strominger J. L., Burakoff S. J., Springer T. A. Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7489–7493. doi: 10.1073/pnas.79.23.7489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sawada M., Suzumura A., Yoshida M., Marunouchi T. Human T-cell leukemia virus type I trans activator induces class I major histocompatibility complex antigen expression in glial cells. J Virol. 1990 Aug;64(8):4002–4006. doi: 10.1128/jvi.64.8.4002-4006.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schneider J., Yamamoto N., Hinuma Y., Hunsmann G. Sera from adult T-cell leukemia patients react with envelope and core polypeptides of adult T-cell leukemia virus. Virology. 1984 Jan 15;132(1):1–11. doi: 10.1016/0042-6822(84)90086-2. [DOI] [PubMed] [Google Scholar]
  35. Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Tanaka Y., Zeng L., Shiraki H., Shida H., Tozawa H. Identification of a neutralization epitope on the envelope gp46 antigen of human T cell leukemia virus type I and induction of neutralizing antibody by peptide immunization. J Immunol. 1991 Jul 1;147(1):354–360. [PubMed] [Google Scholar]
  38. Tendler C. L., Greenberg S. J., Blattner W. A., Manns A., Murphy E., Fleisher T., Hanchard B., Morgan O., Burton J. D., Nelson D. L. Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5218–5222. doi: 10.1073/pnas.87.13.5218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wano Y., Feinberg M., Hosking J. B., Bogerd H., Greene W. C. Stable expression of the tax gene of type I human T-cell leukemia virus in human T cells activates specific cellular genes involved in growth. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9733–9737. doi: 10.1073/pnas.85.24.9733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Weiss A., Imboden J., Hardy K., Manger B., Terhorst C., Stobo J. The role of the T3/antigen receptor complex in T-cell activation. Annu Rev Immunol. 1986;4:593–619. doi: 10.1146/annurev.iy.04.040186.003113. [DOI] [PubMed] [Google Scholar]
  41. Weiss A., Wiskocil R. L., Stobo J. D. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984 Jul;133(1):123–128. [PubMed] [Google Scholar]
  42. Wucherpfennig K. W., Höllsberg P., Richardson J. H., Benjamin D., Hafler D. A. T-cell activation by autologous human T-cell leukemia virus type I-infected T-cell clones. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2110–2114. doi: 10.1073/pnas.89.6.2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. 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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