Abstract
Experiments have been designed to test the hypothesis that soluble mediator production and T-cell-mediated cytotoxicity are necessarily related phenomena, and that soluble mediators may be involved in the mechanism of cytolysis. To this end, agents known to inhibit T-cell-mediated lysis in vitro have been studied for their effects on the production of two lymphocyte-derived mediators, lymphotoxin (LT) and migration inhibitory factor (MIF). A clear dissociation between mediator production and cell-mediated cytolysis was found using inhibitors of protein synthesis. Pactamycin and emetine, in doses of 10–7 M to 10–6 M, suppressed production of MIF and LT with only slight effect on killing of mastocytoma cells by immune T cells. On the other hand colchicine and vinblastine inhibited T-cell-mediated cytolysis in a dose-related manner but had no significant effect on either MIF or LT production, A striking dichotomy was also observed after augmentation of intracellular cyclic 3'5' adenosine monophosphate (cAMP) levels with cholera enterotoxin. Increased cAMP levels were associated with abrogation of direct lytic activity, but were without significant effect on MIF or LT production in guinea pigs or mice. These findings indicate that mediator production and direct lymphocyte-mediated cytolysis can be experimentally dissociated and represent independent cell-mediated immune functions.
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Selected References
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- Bloom B. R., Gaffney J., Jimenez L. Dissociation of MIF production and cell proliferation. J Immunol. 1972 Dec;109(6):1395–1398. [PubMed] [Google Scholar]
- Brown B. L., Albano J. D., Ekins R. P., Sgherzi A. M. A simple and sensitive saturation assay method for the measurement of adenosine 3':5'-cyclic monophosphate. Biochem J. 1971 Feb;121(3):561–562. doi: 10.1042/bj1210561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brunner K. T., Mauel J., Cerottini J. C., Chapuis B. Quantitative assay of the lytic action of immune lymphoid cells on 51-Cr-labelled allogeneic target cells in vitro; inhibition by isoantibody and by drugs. Immunology. 1968 Feb;14(2):181–196. [PMC free article] [PubMed] [Google Scholar]
- David J. R. Suppression of delayed hypersensitivity in vitro by inhibition of protein synthesis. J Exp Med. 1965 Dec 1;122(6):1125–1134. doi: 10.1084/jem.122.6.1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dennert G. Evidence for non-identity of T killer and T helper cells sensitised to allogeneic cell antigens. Nature. 1974 May 24;249(455):358–360. doi: 10.1038/249358a0. [DOI] [PubMed] [Google Scholar]
- Granger G. A., Kolb W. P. Lymphocyte in vitro cytotoxicity: mechanisms of immune and non-immune small lymphocyte mediated target L cell destruction. J Immunol. 1968 Jul;101(1):111–120. [PubMed] [Google Scholar]
- Hadden J. W., Hadden E. M., Haddox M. K., Goldberg N. D. Guanosine 3':5'-cyclic monophosphate: a possible intracellular mediator of mitogenic influences in lymphocytes. Proc Natl Acad Sci U S A. 1972 Oct;69(10):3024–3027. doi: 10.1073/pnas.69.10.3024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henney C. S., Bourne H. R., Lichtenstein L. M. The role of cyclic 3',5' adenosine monophosphate in the specific cytolytic activity of lymphocytes. J Immunol. 1972 Jun;108(6):1526–1534. [PubMed] [Google Scholar]
- Henney C. S., Bubbers J. E. Antigen-T lymphocyte interactions: inhibition by cytochalasin B. J Immunol. 1973 Jul;111(1):85–90. [PubMed] [Google Scholar]
- Henney C. S., Bubbers J. E. Studies on the mechanism of lymphocyte-mediated cytolysis. I. The role of divalent cations in cytolysis by T lymphocytes. J Immunol. 1973 Jan;110(1):63–72. [PubMed] [Google Scholar]
- Henney C. S., Lichtenstein L. M., Gillespie E., Rolley R. T. In vivo suppression of the immune response to alloantigen by cholera enterotoxin. J Clin Invest. 1973 Nov;52(11):2853–2857. doi: 10.1172/JCI107481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henney C. S. On the mechanism of T-cell mediated cytolysis. Transplant Rev. 1973;17(0):37–70. doi: 10.1111/j.1600-065x.1973.tb00123.x. [DOI] [PubMed] [Google Scholar]
- Henney C. S. Quantitation of the cell-mediated immune response. I. The number of cytolytically active mouse lymphoid cells induced by immunization with allogeneic mastocytoma cells. J Immunol. 1971 Dec;107(6):1558–1566. [PubMed] [Google Scholar]
- Häyry P., Defendi V. Mixed lymphocyte cultures produce effector cells: model in vitro for allograft rejection. Science. 1970 Apr 3;168(3927):133–135. doi: 10.1126/science.168.3927.133. [DOI] [PubMed] [Google Scholar]
- Koopman W. J., Gillis M. H., David J. R. Prevention of MIF activity by agents known to increase cellular cyclic AMP. J Immunol. 1973 Jun;110(6):1609–1614. [PubMed] [Google Scholar]
- Lichtenstein L. M., Henney C. S., Bourne H. R., Greenough W. B., 3rd Effects of cholera toxin on in vitro models of immediate and delayed hypersensitivity. Further evidence for the role of cyclic adenosine 3',5'-monophosphate. J Clin Invest. 1973 Mar;52(3):691–697. doi: 10.1172/JCI107230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lies R. B., Peter J. B. Cyclic AMP inhibition of cytotoxin ("lymphotoxin") elaboration by stimulated lymphocytes. Cell Immunol. 1973 Aug;8(2):332–335. doi: 10.1016/0008-8749(73)90123-8. [DOI] [PubMed] [Google Scholar]
- Macdonald J. S., Goldberg I. H. An effect of pactamycin on the initiation of protein synthesis in reticulocytes. Biochem Biophys Res Commun. 1970 Oct 9;41(1):1–8. doi: 10.1016/0006-291x(70)90460-2. [DOI] [PubMed] [Google Scholar]
- Mauel J., Rudolf H., Chapuis B., Brunner K. T. Studies of allograft immunity in mice. II. Mechanism of target cell inactivation in vitro by sensitized lymphocytes. Immunology. 1970 Apr;18(4):517–535. [PMC free article] [PubMed] [Google Scholar]
- Parkhouse R. M., Allison A. C. Failure of cytochalasin or colchicine to inhibit secretion of immunoglobulins. Nat New Biol. 1972 Feb 16;235(59):220–222. doi: 10.1038/newbio235220a0. [DOI] [PubMed] [Google Scholar]
- Perlmann P., Holm G. Cytotoxic effects of lymphoid cells in vitro. Adv Immunol. 1969;11:117–193. doi: 10.1016/s0065-2776(08)60479-4. [DOI] [PubMed] [Google Scholar]
- Plaut M., Lichtenstein L. M., Henney C. S. Studies on the mechanism of lymphocyte-mediated cytolysis. 3. The role of microfilaments and microtubules. J Immunol. 1973 Mar;110(3):771–780. [PubMed] [Google Scholar]
- Rocklin R. E. Production of migration inhibitory factor by non-dividing lymphocytes. J Immunol. 1973 Mar;110(3):674–678. [PubMed] [Google Scholar]
- Ruddle N. H., Waksman B. H. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. 3. Analysis of mechanism. J Exp Med. 1968 Dec 1;128(6):1267–1279. doi: 10.1084/jem.128.6.1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shacks S. J., Chiller J., Granger G. A. Studies on in vitro models of cellular immunity: the role of T and B cells in the secretion of lymphotoxin. Cell Immunol. 1973 May;7(2):313–321. doi: 10.1016/0008-8749(73)90253-0. [DOI] [PubMed] [Google Scholar]
- Strom T. B., Deisseroth A., Morganroth J., Carpenter C. B., Merrill J. P. Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase. Proc Natl Acad Sci U S A. 1972 Oct;69(10):2995–2999. doi: 10.1073/pnas.69.10.2995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strom T. B., Garovoy M. R., Carpenter D. B., Merrill J. P. Microtubule function in immune and nonimmune lymphocyte-mediated cytotoxicity. Science. 1973 Jul 13;181(4095):171–173. doi: 10.1126/science.181.4095.171. [DOI] [PubMed] [Google Scholar]
- Weissmann G., Dukor P., Zurier R. B. Effect of cyclic AMP on release of lysosomal enzymes from phagocytes. Nat New Biol. 1971 Jun 2;231(22):131–135. doi: 10.1038/newbio231131a0. [DOI] [PubMed] [Google Scholar]
- White J. G. Effects of colchicine and vinca alkaloids on human platelets. 3. Influence on primary internal contraction and secondary aggregation. Am J Pathol. 1969 Mar;54(3):467–478. [PMC free article] [PubMed] [Google Scholar]
- Williams T. W., Granger G. A. Lymphocyte in vitro cytotoxicity: correlation of derepression with release of lymphotoxin from human lymphocytes. J Immunol. 1969 Aug;103(2):170–178. [PubMed] [Google Scholar]
- Yoshida T., Sonozaki H., Cohen S. The production of migration inhibition factor by B and T cells of the guinea pig. J Exp Med. 1973 Oct 1;138(4):784–797. doi: 10.1084/jem.138.4.784. [DOI] [PMC free article] [PubMed] [Google Scholar]
