Abstract
To better understand the requirement for interleukin 2 (IL-2) in specific immune responses, we have established the use of cell ablation to selectively eliminate T cells that produce IL-2. To accomplish this we have generated transgenic mice that express the herpes simplex virus 1-thymidine kinase (HSV-TK) gene under the transcriptional control of the murine IL-2 promoter that renders IL-2-producing cells sensitive to the cytotoxic effects of the antiviral drug ganciclovir (GANC). HSV-TK activity was specifically expressed in activated T cells from transgenic mice. When CD4 T cells from transgenic mice were stimulated with the superantigen staphylococcal enterotoxin A (SEA) in the presence of GANC, proliferation and IL-2 production were almost completely inhibited and the activated CD4+V beta 3+ T cell population, eliminated. Proliferation was not restored by adding IL-2, showing that most proliferating cells are not bystander cells. In contrast, the proliferative response to concanavalin A (Con A) was only partially inhibited by treatment of CD4 T cells with GANC, although the efficiency of eliminating IL-2-producing cells was shown to be comparable with that achieved using SEA. This suggests that a portion of the proliferative response to Con A occurs via an alternative pathway not requiring IL-2 synthesis and release.
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Selected References
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- Bottomly K. Subsets of CD4 T cells and B cell activation. Semin Immunol. 1989 Sep;1(1):21–31. [PubMed] [Google Scholar]
- Carding S. R., West J., Woods A., Bottomly K. Differential activation of cytokine genes in normal CD4-bearing T cells is stimulus dependent. Eur J Immunol. 1989 Feb;19(2):231–238. doi: 10.1002/eji.1830190203. [DOI] [PubMed] [Google Scholar]
- Degrave W., Simons G., Devos R., Plaetinck G., Remaut E., Tavernier J., Fiers W. Cloning and structure of a mouse interleukin-2 chromosomal gene. Mol Biol Rep. 1986;11(1):57–61. doi: 10.1007/BF00417597. [DOI] [PubMed] [Google Scholar]
- Greenbaum L. A., Horowitz J. B., Woods A., Pasqualini T., Reich E. P., Bottomly K. Autocrine growth of CD4+ T cells. Differential effects of IL-1 on helper and inflammatory T cells. J Immunol. 1988 Mar 1;140(5):1555–1560. [PubMed] [Google Scholar]
- Harper M. E., Marselle L. M., Gallo R. C., Wong-Staal F. Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc Natl Acad Sci U S A. 1986 Feb;83(3):772–776. doi: 10.1073/pnas.83.3.772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
- Isakov N., Bleackley R. C., Shaw J., Altman A. Teleocidin and phorbol ester tumor promoters exert similar mitogenic effects on human lymphocytes. Biochem Biophys Res Commun. 1985 Jul 31;130(2):724–731. doi: 10.1016/0006-291x(85)90476-0. [DOI] [PubMed] [Google Scholar]
- Jones B. Functional activities of antibodies against brain-associated T cell antigens. II. Stimulation of T cell-induced B cell proliferation. Eur J Immunol. 1982 Jan;12(1):30–37. doi: 10.1002/eji.1830120108. [DOI] [PubMed] [Google Scholar]
- Kim D. K., Otten G., Moldwin R. L., Dunn D. E., Nau G. J., Fitch F. W. PMA alone induces proliferation of some murine T cell clones but not others. J Immunol. 1986 Nov 1;137(9):2755–2760. [PubMed] [Google Scholar]
- Kim J., Woods A., Becker-Dunn E., Bottomly K. Distinct functional phenotypes of cloned Ia-restricted helper T cells. J Exp Med. 1985 Jul 1;162(1):188–201. doi: 10.1084/jem.162.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Laing T. J., Weiss A. Evidence for IL-2 independent proliferation in human T cells. J Immunol. 1988 Feb 15;140(4):1056–1062. [PubMed] [Google Scholar]
- Landias D., Beck B. N., Buerstedde J. M., Degraw S., Klein D., Koch N., Murphy D., Pierres M., Tada T., Yamamoto K. The assignment of chain specificities for anti-Ia monoclonal antibodies using L cell transfectants. J Immunol. 1986 Nov 1;137(9):3002–3005. [PubMed] [Google Scholar]
- Lichtman A. H., Kurt-Jones E. A., Abbas A. K. B-cell stimulatory factor 1 and not interleukin 2 is the autocrine growth factor for some helper T lymphocytes. Proc Natl Acad Sci U S A. 1987 Feb;84(3):824–827. doi: 10.1073/pnas.84.3.824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McKnight S. L. The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Res. 1980 Dec 20;8(24):5949–5964. doi: 10.1093/nar/8.24.5949. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moldwin R. L., Lancki D. W., Herold K. C., Fitch F. W. An antigen receptor-driven, interleukin 2-independent pathway for proliferation of murine cytolytic T lymphocyte clones. J Exp Med. 1986 Jun 1;163(6):1566–1582. doi: 10.1084/jem.163.6.1566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
- Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
- Schorle H., Holtschke T., Hünig T., Schimpl A., Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 1991 Aug 15;352(6336):621–624. doi: 10.1038/352621a0. [DOI] [PubMed] [Google Scholar]
- Siebenlist U., Durand D. B., Bressler P., Holbrook N. J., Norris C. A., Kamoun M., Kant J. A., Crabtree G. R. Promoter region of interleukin-2 gene undergoes chromatin structure changes and confers inducibility on chloramphenicol acetyltransferase gene during activation of T cells. Mol Cell Biol. 1986 Sep;6(9):3042–3049. doi: 10.1128/mcb.6.9.3042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith K. A., Favata M. F., Oroszlan S. Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol. 1983 Oct;131(4):1808–1815. [PubMed] [Google Scholar]
- Smith K. A. Interleukin 2. Annu Rev Immunol. 1984;2:319–333. doi: 10.1146/annurev.iy.02.040184.001535. [DOI] [PubMed] [Google Scholar]
- Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
- Stout R. D., Bottomly K. Antigen-specific activation of effector macrophages by IFN-gamma producing (TH1) T cell clones. Failure of IL-4-producing (TH2) T cell clones to activate effector function in macrophages. J Immunol. 1989 Feb 1;142(3):760–765. [PubMed] [Google Scholar]
- Summers W. C., Summers W. P. [125I]deoxycytidine used in a rapid, sensitive, and specific assay for herpes simplex virus type 1 thymidine kinase. J Virol. 1977 Oct;24(1):314–318. doi: 10.1128/jvi.24.1.314-318.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takimoto H., Yoshikai Y., Kishihara K., Matsuzaki G., Kuga H., Otani T., Nomoto K. Stimulation of all T cells bearing V beta 1, V beta 3, V beta 11 and V beta 12 by staphylococcal enterotoxin A. Eur J Immunol. 1990 Mar;20(3):617–621. doi: 10.1002/eji.1830200323. [DOI] [PubMed] [Google Scholar]
- Widmer M. B., Bach F. H. Antigen-driven helper cell-independent cloned cytolytic T lymphocytes. Nature. 1981 Dec 24;294(5843):750–752. doi: 10.1038/294750a0. [DOI] [PubMed] [Google Scholar]