Journal Article
. 1996 Jul; 184(1):159-64.
doi: 10.1084/jem.184.1.159.

Translational control of interleukin 2 messenger RNA as a molecular mechanism of T cell anergy

J A Garcia-Sanz 1 D Lenig  
  • PMID: 8691129
  •     36 References
  •     10 citations


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.

T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state.
M K Jenkins, D M Pardoll, +2 authors, R H Schwartz.
Immunol Rev, 1987 Feb 01; 95. PMID: 2437012
The role of the T3/antigen receptor complex in T-cell activation.
A Weiss, J Imboden, +3 authors, J Stobo.
Annu Rev Immunol, 1986 Jan 01; 4. PMID: 2939858
Highly Cited. Review.
Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones.
M K Jenkins, D M Pardoll, +2 authors, R H Schwartz.
Proc Natl Acad Sci U S A, 1987 Aug 01; 84(15). PMID: 2955418    Free PMC article.
Highly Cited.
Stepwise activation of T cells. Role of the calcium ionophore A23187.
R L Geller, G Gromo, +2 authors, F H Bach.
J Immunol, 1987 Dec 15; 139(12). PMID: 2826575
Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes.
G Essery, M Feldmann, J R Lamb.
Immunology, 1988 Jul 01; 64(3). PMID: 2457547    Free PMC article.
Contingent genetic regulatory events in T lymphocyte activation.
G R Crabtree.
Science, 1989 Jan 20; 243(4889). PMID: 2783497
Highly Cited.
Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy.
D L Mueller, M K Jenkins, R H Schwartz.
Annu Rev Immunol, 1989 Jan 01; 7. PMID: 2653373
Highly Cited. Review.
A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA.
E W Müllner, B Neupert, L C Kühn.
Cell, 1989 Jul 28; 58(2). PMID: 2752428
Highly Cited.
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.
M Szamel, M Kracht, +2 authors, K Resch.
Cell Immunol, 1990 Mar 01; 126(1). PMID: 2105849
A cell culture model for T lymphocyte clonal anergy.
R H Schwartz.
Science, 1990 Jun 15; 248(4961). PMID: 2113314
Highly Cited.
T-cell clonal anergy.
R H Schwartz, D L Mueller, M K Jenkins, H Quill.
Cold Spring Harb Symp Quant Biol, 1989 Jan 01; 54 Pt 2. PMID: 2534840
CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells.
M K Jenkins, P S Taylor, S D Norton, K B Urdahl.
J Immunol, 1991 Oct 15; 147(8). PMID: 1717561
Highly Cited.
Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation.
D R DeSilva, K B Urdahl, M K Jenkins.
J Immunol, 1991 Nov 15; 147(10). PMID: 1658142
CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones.
F A Harding, J G McArthur, +2 authors, J P Allison.
Nature, 1992 Apr 16; 356(6370). PMID: 1313950
Highly Cited.
Perforin expression in human peripheral blood mononuclear cells. Definition of an IL-2-independent pathway of perforin induction in CD8+ T cells.
P Lu, J A Garcia-Sanz, M G Lichtenheld, E R Podack.
J Immunol, 1992 Jun 01; 148(11). PMID: 1588036
Reversal of in vitro T cell clonal anergy by IL-2 stimulation.
B Beverly, S M Kang, M J Lenardo, R H Schwartz.
Int Immunol, 1992 Jun 01; 4(6). PMID: 1616898
Highly Cited.
Transactivation by AP-1 is a molecular target of T cell clonal anergy.
S M Kang, B Beverly, +3 authors, M J Lenardo.
Science, 1992 Aug 21; 257(5073). PMID: 1509265
Highly Cited.
Evidence for instability of mRNAs containing AUUUA motifs mediated through translation-dependent assembly of a > 20S degradation complex.
S Savant-Bhonsale, D W Cleveland.
Genes Dev, 1992 Oct 01; 6(10). PMID: 1398070
Highly Cited.
Role of transmembrane domain interactions in the assembly of class II MHC molecules.
P Cosson, J S Bonifacino.
Science, 1992 Oct 23; 258(5082). PMID: 1329208
Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy.
R H Schwartz.
Cell, 1992 Dec 24; 71(7). PMID: 1335362
Highly Cited. Review.
Altered protein tyrosine phosphorylation in anergic Th1 cells.
E A Cho, M P Riley, A L Sillman, H Quill.
J Immunol, 1993 Jul 01; 151(1). PMID: 7686931
Regulation of perforin gene expression in a T cell hybrid with inducible cytolytic activity.
J A García-Sanz, E R Podack.
Eur J Immunol, 1993 Aug 01; 23(8). PMID: 8344349
Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy.
J Sloan-Lancaster, A S Shaw, J B Rothbard, P M Allen.
Cell, 1994 Dec 02; 79(5). PMID: 8001128
Highly Cited.
Negative transcriptional regulation in anergic T cells.
J C Becker, T Brabletz, +3 authors, R A Reisfeld.
Proc Natl Acad Sci U S A, 1995 Mar 14; 92(6). PMID: 7892274    Free PMC article.
Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy.
D Wotton, J A Higgins, +2 authors, R A Lake.
Hum Immunol, 1995 Feb 01; 42(2). PMID: 7744623
Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells.
W Li, C D Whaley, A Mondino, D L Mueller.
Science, 1996 Mar 01; 271(5253). PMID: 8638107
Highly Cited.
Blocked Ras activation in anergic CD4+ T cells.
P E Fields, T F Gajewski, F W Fitch.
Science, 1996 Mar 01; 271(5253). PMID: 8638108
Highly Cited.
T cell growth factor: parameters of production and a quantitative microassay for activity.
S Gillis, M M Ferm, W Ou, K A Smith.
J Immunol, 1978 Jun 01; 120(6). PMID: 307029
Highly Cited.
Molecular cloning of a human histocompatibility antigen cDNA fragment.
H L Ploegh, H T Orr, J L Strominger.
Proc Natl Acad Sci U S A, 1980 Oct 01; 77(10). PMID: 6934534    Free PMC article.
Highly Cited.
Polymorphism in mitogenic effect of IgG1 monoclonal antibodies against T3 antigen on human T cells.
W J Tax, H W Willems, +2 authors, R A Koene.
Nature, 1983 Aug 04; 304(5925). PMID: 6224091
Highly Cited.
Structure and expression of the mouse beta 2-microglobulin gene isolated from somatic and non-expressing teratocarcinoma cells.
F Daniel, D Morello, +3 authors, P Kourilsky.
EMBO J, 1983 Jan 01; 2(7). PMID: 6354707    Free PMC article.
Changes in levels of actin and tubulin mRNAs upon the lectin activation of lymphocytes.
E McCairns, D Fahey, +2 authors, P B Rowe.
Mol Cell Biol, 1984 Sep 01; 4(9). PMID: 6548547    Free PMC article.
Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester.
A Truneh, F Albert, P Golstein, A M Schmitt-Verhulst.
Nature, 1985 Jan 24; 313(6000). PMID: 3918270
Highly Cited.
Growth-related changes in specific mRNAs upon lectin activation of human lymphocytes.
G E Muscat, A Caputo, E McCairns, P B Rowe.
DNA, 1985 Oct 01; 4(5). PMID: 3841046
Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates.
S Alonso, A Minty, Y Bourlet, M Buckingham.
J Mol Evol, 1986 Jan 01; 23(1). PMID: 3084797
Highly Cited.
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.
H Quill, R H Schwartz.
J Immunol, 1987 Jun 01; 138(11). PMID: 3035012
Highly Cited.
Abnormal intracellular IL-2 and interferon-gamma (IFN-gamma) production as HIV-1-assocated markers of immune dysfunction.
M Westby, J B Marriott, +3 authors, A G Dalgleish.
Clin Exp Immunol, 1998 Mar 05; 111(2). PMID: 9486390    Free PMC article.
Inhibition of apoptosis by ionomycin and zinc in peripheral blood mononuclear cells (PBMC) of leprosy patients.
A Gupta, V K Sharma, H Vohra, N K Ganguly.
Clin Exp Immunol, 1999 Jul 15; 117(1). PMID: 10403916    Free PMC article.
Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients.
A Grolleau, M J Kaplan, +2 authors, B Richardson.
J Clin Invest, 2000 Dec 20; 106(12). PMID: 11120763    Free PMC article.
Isolation of polysome-bound mRNA from solid tissues amenable for RT-PCR and profiling experiments.
M Julieta del Prete, Rolando Vernal, +2 authors, Jose A Garcia-Sanz.
RNA, 2007 Jan 24; 13(3). PMID: 17237355    Free PMC article.
Immune reconstitution after autologous hematopoietic transplantation with Lin-, CD34+, Thy-1lo selected or intact stem cell products.
Rakesh K Singh, Michelle L Varney, +9 authors, James E Talmadge.
Int Immunopharmacol, 2007 Jun 16; 7(8). PMID: 17570320    Free PMC article.
Digital NFATc2 activation per cell transforms graded T cell receptor activation into an all-or-none IL-2 expression.
Miriam Podtschaske, Uwe Benary, +3 authors, Ria Baumgrass.
PLoS One, 2007 Sep 27; 2(9). PMID: 17895976    Free PMC article.
Function of the nucleotide exchange activity of vav1 in T cell development and activation.
Alexander Saveliev, Lesley Vanes, +4 authors, Victor L J Tybulewicz.
Sci Signal, 2009 Dec 17; 2(101). PMID: 20009105    Free PMC article.
Posttranscriptional silencing of effector cytokine mRNA underlies the anergic phenotype of self-reactive T cells.
Alejandro V Villarino, Shoshana D Katzman, +4 authors, Abul K Abbas.
Immunity, 2011 Jan 18; 34(1). PMID: 21236706    Free PMC article.
Posttranscriptional control of T cell effector function by aerobic glycolysis.
Chih-Hao Chang, Jonathan D Curtis, +11 authors, Erika L Pearce.
Cell, 2013 Jun 12; 153(6). PMID: 23746840    Free PMC article.
Highly Cited.
Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody.
Randi B Gombos, Ana Gonzalez, +24 authors, Nicholas S Wilson.
PLoS One, 2018 Apr 05; 13(4). PMID: 29617360    Free PMC article.