Abstract
T cell stimulation by triggering through the T cell receptor (TCR) in the absence of costimulatory signals or by calcium ionophore induces unresponsiveness in T cells to further stimulation, a phenomenon known as anergy. In freshly isolated T cells, calcium ionophore induces expression of interleukin (IL)-2 messenger (mRNA), but this mRNA is not translated and not loaded with ribosomes. In addition, while plate- bound anti-CD3 stimulation of resting T cells leads to IL-2 mRNA expression and IL-2 secretion, in cells pretreated with calcium ionophore before anti-CD3 stimulation, the IL-2 mRNA remains polysome unloaded and no IL-2 is produced. These observations show that IL-2 expression is controlled at the translational level, by differential ribosome loading. Furthermore, our data suggest that translational control of IL-2 mRNA may be a molecular mechanism by which anergy is attained.
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- Alonso S., Minty A., Bourlet Y., Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. doi: 10.1007/BF02100994. [DOI] [PubMed] [Google Scholar]
- Becker J. C., Brabletz T., Kirchner T., Conrad C. T., Bröcker E. B., Reisfeld R. A. Negative transcriptional regulation in anergic T cells. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2375–2378. doi: 10.1073/pnas.92.6.2375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beverly B., Kang S. M., Lenardo M. J., Schwartz R. H. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol. 1992 Jun;4(6):661–671. doi: 10.1093/intimm/4.6.661. [DOI] [PubMed] [Google Scholar]
- Cho E. A., Riley M. P., Sillman A. L., Quill H. Altered protein tyrosine phosphorylation in anergic Th1 cells. J Immunol. 1993 Jul 1;151(1):20–28. [PubMed] [Google Scholar]
- Cosson P., Bonifacino J. S. Role of transmembrane domain interactions in the assembly of class II MHC molecules. Science. 1992 Oct 23;258(5082):659–662. doi: 10.1126/science.1329208. [DOI] [PubMed] [Google Scholar]
- 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]
- Daniel F., Morello D., Le Bail O., Chambon P., Cayre Y., Kourilsky P. Structure and expression of the mouse beta 2-microglobulin gene isolated from somatic and non-expressing teratocarcinoma cells. EMBO J. 1983;2(7):1061–1065. doi: 10.1002/j.1460-2075.1983.tb01546.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DeSilva D. R., Urdahl K. B., Jenkins M. K. Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation. J Immunol. 1991 Nov 15;147(10):3261–3267. [PubMed] [Google Scholar]
- Essery G., Feldmann M., Lamb J. R. Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology. 1988 Jul;64(3):413–417. [PMC free article] [PubMed] [Google Scholar]
- Fields P. E., Gajewski T. F., Fitch F. W. Blocked Ras activation in anergic CD4+ T cells. Science. 1996 Mar 1;271(5253):1276–1278. doi: 10.1126/science.271.5253.1276. [DOI] [PubMed] [Google Scholar]
- García-Sanz J. A., Podack E. R. Regulation of perforin gene expression in a T cell hybrid with inducible cytolytic activity. Eur J Immunol. 1993 Aug;23(8):1877–1883. doi: 10.1002/eji.1830230822. [DOI] [PubMed] [Google Scholar]
- Geller R. L., Gromo G., Inverardi L., Ferrero E., Bach F. H. Stepwise activation of T cells. Role of the calcium ionophore A23187. J Immunol. 1987 Dec 15;139(12):3930–3934. [PubMed] [Google Scholar]
- Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
- Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
- Jenkins M. K., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jenkins M. K., Pardoll D. M., Mizuguchi J., Quill H., Schwartz R. H. T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol Rev. 1987 Feb;95:113–135. doi: 10.1111/j.1600-065x.1987.tb00502.x. [DOI] [PubMed] [Google Scholar]
- Jenkins M. K., Taylor P. S., Norton S. D., Urdahl K. B. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991 Oct 15;147(8):2461–2466. [PubMed] [Google Scholar]
- Kang S. M., Beverly B., Tran A. C., Brorson K., Schwartz R. H., Lenardo M. J. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992 Aug 21;257(5073):1134–1138. doi: 10.1126/science.257.5073.1134. [DOI] [PubMed] [Google Scholar]
- Li W., Whaley C. D., Mondino A., Mueller D. L. Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells. Science. 1996 Mar 1;271(5253):1272–1276. doi: 10.1126/science.271.5253.1272. [DOI] [PubMed] [Google Scholar]
- Lu P., Garcia-Sanz J. A., Lichtenheld M. G., Podack E. R. Perforin expression in human peripheral blood mononuclear cells. Definition of an IL-2-independent pathway of perforin induction in CD8+ T cells. J Immunol. 1992 Jun 1;148(11):3354–3360. [PubMed] [Google Scholar]
- McCairns E., Fahey D., Muscat G. E., Murray M., Rowe P. B. Changes in levels of actin and tubulin mRNAs upon the lectin activation of lymphocytes. Mol Cell Biol. 1984 Sep;4(9):1754–1760. doi: 10.1128/mcb.4.9.1754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
- Muscat G. E., Caputo A., McCairns E., Rowe P. B. Growth-related changes in specific mRNAs upon lectin activation of human lymphocytes. DNA. 1985 Oct;4(5):377–384. doi: 10.1089/dna.1985.4.377. [DOI] [PubMed] [Google Scholar]
- Müllner E. W., Neupert B., Kühn L. C. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA. Cell. 1989 Jul 28;58(2):373–382. doi: 10.1016/0092-8674(89)90851-9. [DOI] [PubMed] [Google Scholar]
- Ploegh H. L., Orr H. T., Strominger J. L. Molecular cloning of a human histocompatibility antigen cDNA fragment. Proc Natl Acad Sci U S A. 1980 Oct;77(10):6081–6085. doi: 10.1073/pnas.77.10.6081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
- Savant-Bhonsale S., Cleveland D. W. Evidence for instability of mRNAs containing AUUUA motifs mediated through translation-dependent assembly of a > 20S degradation complex. Genes Dev. 1992 Oct;6(10):1927–1939. doi: 10.1101/gad.6.10.1927. [DOI] [PubMed] [Google Scholar]
- Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
- Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
- Schwartz R. H., Mueller D. L., Jenkins M. K., Quill H. T-cell clonal anergy. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 2):605–610. doi: 10.1101/sqb.1989.054.01.072. [DOI] [PubMed] [Google Scholar]
- Sloan-Lancaster J., Shaw A. S., Rothbard J. B., Allen P. M. Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy. Cell. 1994 Dec 2;79(5):913–922. doi: 10.1016/0092-8674(94)90080-9. [DOI] [PubMed] [Google Scholar]
- Szamel M., Kracht M., Krebs B., Hübner U., Resch K. Activation signals in human lymphocytes: interleukin 2 synthesis and expression of high affinity interleukin 2 receptors require differential signalling for the activation of protein kinase C. Cell Immunol. 1990 Mar;126(1):117–128. doi: 10.1016/0008-8749(90)90305-b. [DOI] [PubMed] [Google Scholar]
- Tax W. J., Willems H. W., Reekers P. P., Capel P. J., Koene R. A. Polymorphism in mitogenic effect of IgG1 monoclonal antibodies against T3 antigen on human T cells. Nature. 1983 Aug 4;304(5925):445–447. doi: 10.1038/304445a0. [DOI] [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]
- 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]
- Wotton D., Higgins J. A., O'Hehir R. E., Lamb J. R., Lake R. A. Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy. Hum Immunol. 1995 Feb;42(2):95–102. doi: 10.1016/0198-8859(94)00004-a. [DOI] [PubMed] [Google Scholar]