Abstract
CD4+ T helper (Th) clones can be divided into interleukin 2 (IL-2)- secreting Th1 and IL-4-secreting Th2 cells. We show in the present report that these two Th subsets have different activation requirements for lymphokine production and proliferation: namely, cholera toxin (CT) as well as forskolin inhibit T cell receptor (TCR)-mediated IL-2 production and proliferation in Th1 cells, while the same reagents fail to block IL-4 production and proliferation in Th2 cells. In addition, CT and forskolin differentially influence the proto-oncogene mRNA expression in Th1 vs. Th2 cells after stimulation with Con A. Since both reagents lead to elevated levels of intracellular cAMP, it is likely that Th1 and Th2 cells differ in their sensitivity to an increase in cAMP. Our results indicate that the two Th subsets use different transmission signal pathways upon TCR-mediated activation.
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- Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
- Bennett C. F., Crooke S. T. Purification and characterization of a phosphoinositide-specific phospholipase C from guinea pig uterus. Phosphorylation by protein kinase C in vivo. J Biol Chem. 1987 Oct 5;262(28):13789–13797. [PubMed] [Google Scholar]
- Carafoli E. Intracellular calcium homeostasis. Annu Rev Biochem. 1987;56:395–433. doi: 10.1146/annurev.bi.56.070187.002143. [DOI] [PubMed] [Google Scholar]
- Chilson O. P., Kelly-Chilson A. E. Mitogenic lectins bind to the antigen receptor on human lymphocytes. Eur J Immunol. 1989 Feb;19(2):389–396. doi: 10.1002/eji.1830190225. [DOI] [PubMed] [Google Scholar]
- Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Churilla A. M., Braciale T. J., Braciale V. L. Regulation of T lymphocyte proliferation. Interleukin 2-mediated induction of c-myb gene expression is dependent on T lymphocyte activation state. J Exp Med. 1989 Jul 1;170(1):105–121. doi: 10.1084/jem.170.1.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deutsch P. J., Hoeffler J. P., Jameson J. L., Habener J. F. Cyclic AMP and phorbol ester-stimulated transcription mediated by similar DNA elements that bind distinct proteins. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7922–7926. doi: 10.1073/pnas.85.21.7922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Farrar W. L., Evans S. W., Rapp U. R., Cleveland J. L. Effects of anti-proliferative cyclic AMP on interleukin 2-stimulated gene expression. J Immunol. 1987 Sep 15;139(6):2075–2080. [PubMed] [Google Scholar]
- Gewirtz A. M., Anfossi G., Venturelli D., Valpreda S., Sims R., Calabretta B. G1/S transition in normal human T-lymphocytes requires the nuclear protein encoded by c-myb. Science. 1989 Jul 14;245(4914):180–183. doi: 10.1126/science.2665077. [DOI] [PubMed] [Google Scholar]
- Gilbert K. M., Hoffmann M. K. cAMP is an essential signal in the induction of antibody production by B cells but inhibits helper function of T cells. J Immunol. 1985 Sep;135(3):2084–2089. [PubMed] [Google Scholar]
- Gill D. M., Meren R. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3050–3054. doi: 10.1073/pnas.75.7.3050. [DOI] [PMC free article] [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]
- Hadden J. W. Transmembrane signals in the activation of T lymphocytes by mitogenic antigens. Immunol Today. 1988 Jul-Aug;9(7-8):235–239. doi: 10.1016/0167-5699(88)91222-4. [DOI] [PubMed] [Google Scholar]
- Hayari Y., Kukulansky T., Globerson A. Regulation of thymocyte proliferative response by macrophage-derived prostaglandin E2 and interleukin 1. Eur J Immunol. 1985 Jan;15(1):43–47. doi: 10.1002/eji.1830150109. [DOI] [PubMed] [Google Scholar]
- Heikkila R., Schwab G., Wickstrom E., Loke S. L., Pluznik D. H., Watt R., Neckers L. M. A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1. 1987 Jul 30-Aug 5Nature. 328(6129):445–449. doi: 10.1038/328445a0. [DOI] [PubMed] [Google Scholar]
- Isakov N., Mally M. I., Scholz W., Altman A. T-lymphocyte activation: the role of protein kinase C and the bifurcating inositol phospholipid signal transduction pathway. Immunol Rev. 1987 Feb;95:89–111. doi: 10.1111/j.1600-065x.1987.tb00501.x. [DOI] [PubMed] [Google Scholar]
- Kaye J., Porcelli S., Tite J., Jones B., Janeway C. A., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. doi: 10.1084/jem.158.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
- Kikkawa U., Nishizuka Y. The role of protein kinase C in transmembrane signalling. Annu Rev Cell Biol. 1986;2:149–178. doi: 10.1146/annurev.cb.02.110186.001053. [DOI] [PubMed] [Google Scholar]
- Kim D. K., Lancki D. W., Hui F. H., Fitch F. W. Protein kinase C-dependent and -independent mechanisms of cloned murine T cell proliferation. The role of protein kinase C translocation and protein kinase C activity. J Immunol. 1989 Jan 15;142(2):616–622. [PubMed] [Google Scholar]
- Kim D. K., Nau G. J., Lancki D. W., Dawson G., Fitch F. W. Cholera toxin discriminates between murine T lymphocyte proliferation stimulated by activators of protein kinase C and proliferation stimulated by IL-2. Possible role for intracellular cAMP. J Immunol. 1988 Nov 15;141(10):3429–3437. [PubMed] [Google Scholar]
- Kovacs E. J., Oppenheim J. J., Young H. A. Induction of c-fos and c-myc expression in T lymphocytes after treatment with recombinant interleukin 1-alpha. J Immunol. 1986 Dec 1;137(11):3649–3651. [PubMed] [Google Scholar]
- Kurt-Jones E. A., Hamberg S., Ohara J., Paul W. E., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness. J Exp Med. 1987 Dec 1;166(6):1774–1787. doi: 10.1084/jem.166.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lichtman A. H., Chin J., Schmidt J. A., Abbas A. K. Role of interleukin 1 in the activation of T lymphocytes. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9699–9703. doi: 10.1073/pnas.85.24.9699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lohmann S. M., Walter U. Regulation of the cellular and subcellular concentrations and distribution of cyclic nucleotide-dependent protein kinases. Adv Cyclic Nucleotide Protein Phosphorylation Res. 1984;18:63–117. [PubMed] [Google Scholar]
- Meuer S. C., Schlossman S. F., Reinherz E. L. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4395–4399. doi: 10.1073/pnas.79.14.4395. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mills G. B., Girard P., Grinstein S., Gelfand E. W. Interleukin-2 induces proliferation of T lymphocyte mutants lacking protein kinase C. Cell. 1988 Oct 7;55(1):91–100. doi: 10.1016/0092-8674(88)90012-8. [DOI] [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]
- Muegge K., Williams T. M., Kant J., Karin M., Chiu R., Schmidt A., Siebenlist U., Young H. A., Durum S. K. Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1. Science. 1989 Oct 13;246(4927):249–251. doi: 10.1126/science.2799385. [DOI] [PubMed] [Google Scholar]
- Muñoz E., Beutner U., Zubiaga A., Huber B. T. IL-1 activates two separate signal transduction pathways in T helper type II cells. J Immunol. 1990 Feb 1;144(3):964–969. [PubMed] [Google Scholar]
- Neer E. J., Clapham D. E. Roles of G protein subunits in transmembrane signalling. Nature. 1988 May 12;333(6169):129–134. doi: 10.1038/333129a0. [DOI] [PubMed] [Google Scholar]
- Otte A. P., van Run P., Heideveld M., van Driel R., Durston A. J. Neural induction is mediated by cross-talk between the protein kinase C and cyclic AMP pathways. Cell. 1989 Aug 25;58(4):641–648. doi: 10.1016/0092-8674(89)90099-8. [DOI] [PubMed] [Google Scholar]
- Pardee A. B. G1 events and regulation of cell proliferation. Science. 1989 Nov 3;246(4930):603–608. doi: 10.1126/science.2683075. [DOI] [PubMed] [Google Scholar]
- Roehm N. W., Leibson H. J., Zlotnik A., Kappler J., Marrack P., Cambier J. C. Interleukin-induced increase in Ia expression by normal mouse B cells. J Exp Med. 1984 Sep 1;160(3):679–694. doi: 10.1084/jem.160.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schneider-Schaulies J., Schimpl A., Wecker E. Kinetics of cellular oncogene expression in mouse lymphocytes. II. Regulation of c-fos and c-myc gene expression. Eur J Immunol. 1987 May;17(5):713–718. doi: 10.1002/eji.1830170521. [DOI] [PubMed] [Google Scholar]
- Shaw J. P., Utz P. J., Durand D. B., Toole J. J., Emmel E. A., Crabtree G. R. Identification of a putative regulator of early T cell activation genes. Science. 1988 Jul 8;241(4862):202–205. doi: 10.1126/science.3260404. [DOI] [PubMed] [Google Scholar]
- Shipp M. A., Reinherz E. L. Differential expression of nuclear proto-oncogenes in T cells triggered with mitogenic and nonmitogenic T3 and T11 activation signals. J Immunol. 1987 Oct 1;139(7):2143–2148. [PubMed] [Google Scholar]
- Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
- Street N. E., Schumacher J. H., Fong T. A., Bass H., Fiorentino D. F., Leverah J. A., Mosmann T. R. Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol. 1990 Mar 1;144(5):1629–1639. [PubMed] [Google Scholar]
- Tartakovsky B., Finnegan A., Muegge K., Brody D. T., Kovacs E. J., Smith M. R., Berzofsky J. A., Young H. A., Durum S. K. IL-1 is an autocrine growth factor for T cell clones. J Immunol. 1988 Dec 1;141(11):3863–3867. [PubMed] [Google Scholar]
- Tony H. P., Phillips N. E., Parker D. C. Role of membrane immunoglobulin (Ig) crosslinking in membrane Ig-mediated, major histocompatibility-restricted T cell-B cell cooperation. J Exp Med. 1985 Nov 1;162(5):1695–1708. doi: 10.1084/jem.162.5.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Truneh A., Albert F., Golstein P., Schmitt-Verhulst A. M. Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester. Nature. 1985 Jan 24;313(6000):318–320. doi: 10.1038/313318a0. [DOI] [PubMed] [Google Scholar]
- Unanue E. R. Antigen-presenting function of the macrophage. Annu Rev Immunol. 1984;2:395–428. doi: 10.1146/annurev.iy.02.040184.002143. [DOI] [PubMed] [Google Scholar]
- Valge V. E., Wong J. G., Datlof B. M., Sinskey A. J., Rao A. Protein kinase C is required for responses to T cell receptor ligands but not to interleukin-2 in T cells. Cell. 1988 Oct 7;55(1):101–112. doi: 10.1016/0092-8674(88)90013-x. [DOI] [PubMed] [Google Scholar]
- Woogen S. D., Ealding W., Elson C. O. Inhibition of murine lymphocyte proliferation by the B subunit of cholera toxin. J Immunol. 1987 Dec 1;139(11):3764–3770. [PubMed] [Google Scholar]