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. 1987 Oct 1;166(4):991–998. doi: 10.1084/jem.166.4.991

Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha

PMCID: PMC2188710  PMID: 3498791

Abstract

The immunoregulatory effects of transforming growth factor beta (TGF- beta) and recombinant murine tumor necrosis factor alpha (rMuTNF-alpha) on CTL generation and activity were examined. The results demonstrate that TGF-beta, in a dose-dependent manner, inhibited CTL generation but not CTL activity. The inhibitory effects were detected only when TGF- beta was added within the first 48 h of the MLC. Little activity was seen when it was added thereafter, including the addition of TGF-beta to the cytotoxicity assay. The production of TNF-alpha, which occurs during early phases of the MLC and which is inhibited in the presence of TGF-beta, appears to have an important regulatory role, as altering the levels of TNF-alpha in an MLC can significantly influence CTL development. The inhibitory effects of TGF-beta on the MLC can be significantly reversed by the addition of rMuTNF-alpha to the cultures. These results demonstrate that TGF-beta can inhibit MLC and subsequent CTL generation at early stages of the reaction, and such inhibition may involve the suppression of TNF-alpha production.

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Selected References

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

  1. Abbott J., Doyle P. J., Ngiam K., Olson C. L. Ontogeny of murine T lymphocytes. I. Maturation of thymocytes induced in vitro by tumor necrosis factor-positive serum (TNF+)1,2. Cell Immunol. 1981 Jan 1;57(1):237–250. doi: 10.1016/0008-8749(81)90136-2. [DOI] [PubMed] [Google Scholar]
  2. Derynck R., Rhee L. Sequence of the porcine transforming growth factor-beta precursor. Nucleic Acids Res. 1987 Apr 10;15(7):3187–3187. doi: 10.1093/nar/15.7.3187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Espevik T., Figari I. S., Shalaby M. R., Lackides G. A., Lewis G. D., Shepard H. M., Palladino M. A., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. doi: 10.1084/jem.166.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Espevik T., Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods. 1986 Dec 4;95(1):99–105. doi: 10.1016/0022-1759(86)90322-4. [DOI] [PubMed] [Google Scholar]
  5. Gately M. K., Wilson D. E., Wong H. L. Synergy between recombinant interleukin 2 (rIL 2) and IL 2-depleted lymphokine-containing supernatants in facilitating allogeneic human cytolytic T lymphocyte responses in vitro. J Immunol. 1986 Feb 15;136(4):1274–1282. [PubMed] [Google Scholar]
  6. Gray P. W., Aggarwal B. B., Benton C. V., Bringman T. S., Henzel W. J., Jarrett J. A., Leung D. W., Moffat B., Ng P., Svedersky L. P. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature. 1984 Dec 20;312(5996):721–724. doi: 10.1038/312721a0. [DOI] [PubMed] [Google Scholar]
  7. Kanagawa O., Chiller J. M. Lymphokine-mediated induction of cytolytic activity in a T cell hybridoma. J Immunol. 1985 Jan;134(1):397–403. [PubMed] [Google Scholar]
  8. Kehrl J. H., Roberts A. B., Wakefield L. M., Jakowlew S., Sporn M. B., Fauci A. S. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed] [Google Scholar]
  9. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Männel D. N., Falk W., Dröge W. Induction of cytotoxic T cell function requires sequential action of three different lymphokines. J Immunol. 1983 Jun;130(6):2508–2510. [PubMed] [Google Scholar]
  11. Nedwin G. E., Svedersky L. P., Bringman T. S., Palladino M. A., Jr, Goeddel D. V. Effect of interleukin 2, interferon-gamma, and mitogens on the production of tumor necrosis factors alpha and beta. J Immunol. 1985 Oct;135(4):2492–2497. [PubMed] [Google Scholar]
  12. Pennica D., Hayflick J. S., Bringman T. S., Palladino M. A., Goeddel D. V. Cloning and expression in Escherichia coli of the cDNA for murine tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6060–6064. doi: 10.1073/pnas.82.18.6060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  14. Peters P. M., Ortaldo J. R., Shalaby M. R., Svedersky L. P., Nedwin G. E., Bringman T. S., Hass P. E., Aggarwal B. B., Herberman R. B., Goeddel D. V. Natural killer-sensitive targets stimulate production of TNF-alpha but not TNF-beta (lymphotoxin) by highly purified human peripheral blood large granular lymphocytes. J Immunol. 1986 Oct 15;137(8):2592–2598. [PubMed] [Google Scholar]
  15. Ristow H. J. BSC-1 growth inhibitor/type beta transforming growth factor is a strong inhibitor of thymocyte proliferation. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5531–5533. doi: 10.1073/pnas.83.15.5531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Scheurich P., Thoma B., Ucer U., Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol. 1987 Mar 15;138(6):1786–1790. [PubMed] [Google Scholar]
  17. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  18. Sugarman B. J., Aggarwal B. B., Hass P. E., Figari I. S., Palladino M. A., Jr, Shepard H. M. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985 Nov 22;230(4728):943–945. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  19. Yang S. S., Malek T. R., Hargrove M. E., Ting C. C. Lymphokine-induced cytotoxicity: requirement of two lymphokines for the induction of optimal cytotoxic response. J Immunol. 1985 Jun;134(6):3912–3919. [PubMed] [Google Scholar]

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