Home LiteratureArticle Details
PMID: 10727454 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Activation-induced inhibition of interleukin 6-mediated T cell survival and signal transducer and activator of transcription 1 signaling.

The Journal of experimental medicine ·Vol. 191 ·No. 6 ·2000-03-20 ·Pages 915-26

Teague TK, Schaefer BC, Hildeman D, Bender J, Mitchell T, Kappler JW, Marrack P

Abstract

The cytokines interleukin (IL)-2, IL-4, IL-6, IL-7, and IL-15 have all previously been shown to inhibit resting T cell death in vitro. We have found a difference in the response of T cells to IL-6, depending on the activation status of the cells. IL-6 inhibited the death of naive T cells, but had no effect on the death of either superantigen-activated T cells, or T cells bearing memory markers. This was true even when the resting and activated T cells were isolated from the same animal; thus, the determining factor for IL-6 insensitivity was the activation status or activation history of the cell, and not the milieu in the animal from which the cells were isolated. Activated T cells expressed lower levels of IL-6 receptors on their surfaces, yet there were sufficient levels of receptors for signaling, as we observed similar levels of signal transducer and activator of transcription (Stat)3 phosphorylation in resting and activated T cells treated with IL-6. However, there was profound inhibition of IL-6-induced Stat1 phosphorylation in activated T cells compared with resting T cells. These data suggest that there is activation-induced inhibition of IL-6 receptor signaling in T cells. This inhibition appears to be specific for some but not all of the IL-6-mediated signaling cascades in these cells.

MeSH Terms
Animals Carrier Proteins/biosynthesis Cell Death/immunology Cell Survival/immunology Cells, Cultured Cytokines/physiology DNA-Binding Proteins/antagonists & inhibitors,metabolism Dose-Response Relationship, Immunologic Down-Regulation/immunology Female Immunologic Memory Immunophenotyping Interleukin-6/antagonists & inhibitors,physiology Interphase/immunology Lymphocyte Activation Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Phosphorylation Receptors, Interleukin-6/antagonists & inhibitors,biosynthesis Repressor Proteins STAT1 Transcription Factor STAT3 Transcription Factor Signal Transduction/immunology Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins T-Lymphocyte Subsets/cytology,immunology,metabolism Trans-Activators/antagonists & inhibitors,metabolism Transcription Factor AP-1/antagonists & inhibitors,physiology
Chemicals
Carrier Proteins Cytokines DNA-Binding Proteins Interleukin-6 Receptors, Interleukin-6 Repressor Proteins STAT1 Transcription Factor STAT3 Transcription Factor Socs1 protein, mouse Stat1 protein, mouse Stat3 protein, mouse Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins Trans-Activators Transcription Factor AP-1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Teague T K
Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Schaefer B C
Hildeman D
Bender J
Mitchell T
Kappler J W
Marrack P
References (67)
67 references, click to expand
  1. STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase.
    Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6915-9 PMID: 7624343
  2. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation.
    Cell. 1995 Jul 28;82(2):241-50 PMID: 7543024
  3. Induction of apoptosis in mature T cells by tumour necrosis factor.
    Nature. 1995 Sep 28;377(6547):348-51 PMID: 7566090
  4. Type I interferons keep activated T cells alive.
    J Exp Med. 1999 Feb 1;189(3):521-30 PMID: 9927514
  5. Bystander virus infection prolongs activated T cell survival.
    J Immunol. 1999 Apr 15;162(8):4527-35 PMID: 10201991
  6. Reactive oxygen species regulate activation-induced T cell apoptosis.
    Immunity. 1999 Jun;10(6):735-44 PMID: 10403648
  7. Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigen.
    J Immunol. 1993 May 1;150(9):3785-92 PMID: 8473733
  8. Costimulation of CD3/TcR complex with either integrin or nonintegrin ligands protects CD4+ allergen-specific T-cell clones from programmed cell death.
    Allergy. 1995 Aug;50(8):677-82 PMID: 7503404
  9. Production of interleukin-6 by human mast cells and basophilic cells.
    J Invest Dermatol. 1996 Jan;106(1):75-9 PMID: 8592085
  10. CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response.
    J Immunol. 1996 Mar 1;156(5):1788-98 PMID: 8596028
  11. Differential effects of costimulator signals and interleukin-2 on T cell receptor-mediated cell death of resting and activated CD4+ murine splenic T cells.
    Transplantation. 1996 Feb 15;61(3):486-91 PMID: 8610365
  12. The Janus protein tyrosine kinase family and its role in cytokine signaling.
    Adv Immunol. 1995;60:1-35 PMID: 8607368
  13. Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression.
    Eur J Immunol. 1996 Feb;26(2):294-9 PMID: 8617294
  14. MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span.
    Immunity. 1996 Sep;5(3):217-28 PMID: 8808677
  15. Proteasome- and p53-dependent masking of signal transducer and activator of transcription (STAT) factors.
    J Biol Chem. 1997 Feb 21;272(8):4659-62 PMID: 9030516
  16. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.
    J Exp Med. 1997 Feb 3;185(3):461-9 PMID: 9053446
  17. Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3.
    Nucleic Acids Res. 1997 Jun 1;25(11):2062-7 PMID: 9153303
  18. IL-6 rescues resting mouse T cells from apoptosis.
    J Immunol. 1997 Jun 15;158(12):5791-6 PMID: 9190930
  19. A family of cytokine-inducible inhibitors of signalling.
    Nature. 1997 Jun 26;387(6636):917-21 PMID: 9202125
  20. A new protein containing an SH2 domain that inhibits JAK kinases.
    Nature. 1997 Jun 26;387(6636):921-4 PMID: 9202126
  21. Structure and function of a new STAT-induced STAT inhibitor.
    Nature. 1997 Jun 26;387(6636):924-9 PMID: 9202127
  22. Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4.
    J Exp Med. 1997 Jul 21;186(2):325-30 PMID: 9221762
  23. Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3.
    Biochem Biophys Res Commun. 1997 Aug 8;237(1):79-83 PMID: 9266833
  24. Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules.
    J Exp Med. 1997 Oct 20;186(8):1269-75 PMID: 9334366
  25. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation.
    Mol Cell Biol. 1997 Nov;17(11):6508-16 PMID: 9343414
  26. SOCS-1/JAB/SSI-1 can bind to and suppress Tec protein-tyrosine kinase.
    J Biol Chem. 1997 Oct 24;272(43):27178-82 PMID: 9341160
  27. Specific inhibition of Stat3 signal transduction by PIAS3.
    Science. 1997 Dec 5;278(5344):1803-5 PMID: 9388184
  28. Twenty proteins containing a C-terminal SOCS box form five structural classes.
    Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):114-9 PMID: 9419338
  29. Cytokine-induced survival of activated T cells in vitro and in vivo.
    Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3810-5 PMID: 9520449
  30. A rapid method for the isolation of functional thymus-derived murine lymphocytes.
    Eur J Immunol. 1973 Oct;3(10):645-9 PMID: 4587740
  31. IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells.
    Lymphokine Res. 1986 Fall;5(4):289-99 PMID: 2946903
  32. Monocyte-derived human B-cell growth factor identified as interferon-beta 2 (BSF-2, IL-6).
    Science. 1988 Jan 29;239(4839):502-4 PMID: 2829354
  33. Down-regulation of homing receptors after T cell activation.
    J Immunol. 1988 Dec 15;141(12):4110-7 PMID: 3058798
  34. Accessory signals in murine cytolytic T cell responses. Dual requirement for IL-1 and IL-6.
    J Immunol. 1989 Sep 15;143(6):1894-8 PMID: 2528583
  35. Activation-driven T cell death. I. Requirements for de novo transcription and translation and association with genome fragmentation.
    J Immunol. 1989 Dec 1;143(11):3461-9 PMID: 2479679
  36. High- and low-affinity receptors for murine interleukin 6. Distinct distribution on B and T cells.
    Eur J Immunol. 1989 Nov;19(11):2107-14 PMID: 2574680
  37. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B.
    Nature. 1991 Jan 17;349(6306):245-8 PMID: 1670963
  38. The surface phenotype of activated T lymphocytes.
    Immunol Cell Biol. 1988 Aug;66 ( Pt 4):297-306 PMID: 2979010
  39. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis.
    Nature. 1991 Oct 31;353(6347):858-61 PMID: 1944559
  40. IL-6 enhances the generation of cytolytic T lymphocytes in the allogeneic mixed leucocyte reaction.
    Clin Exp Immunol. 1992 Jul;89(1):148-53 PMID: 1385765
  41. Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines.
    J Biol Chem. 1992 Sep 15;267(26):18278-83 PMID: 1526968
  42. Role of IL-6, IL-2, and IL-4 in the in vitro induction of cytotoxic T cells.
    J Immunol. 1992 Nov 15;149(10):3316-20 PMID: 1431108
  43. The life span of naive alpha/beta T cells in secondary lymphoid organs.
    J Exp Med. 1993 Apr 1;177(4):891-6 PMID: 8459219
  44. Regulation of IL-6 signaling by p53: STAT3- and STAT5-masking in p53-Val135-containing human hepatoma Hep3B cell lines.
    J Immunol. 1998 Jul 1;161(1):325-34 PMID: 9647240
  45. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway.
    Biochem J. 1998 Sep 1;334 ( Pt 2):297-314 PMID: 9716487
  46. Inhibition of Stat1-mediated gene activation by PIAS1.
    Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10626-31 PMID: 9724754
  47. Religation of the T cell receptor after primary activation of mature T cells inhibits proliferation and induces apoptotic cell death.
    J Immunol. 1993 Jun 15;150(12):5704-15 PMID: 8515084
  48. The age-associated increase in IFN-gamma synthesis by mouse CD8+ T cells correlates with shifts in the frequencies of cell subsets defined by membrane CD44, CD45RB, 3G11, and MEL-14 expression.
    J Immunol. 1993 Jul 15;151(2):575-87 PMID: 7687616
  49. Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes.
    Immunol Today. 1993 Jul;14(7):338-9 PMID: 8363721
  50. Production of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes.
    J Neuroimmunol. 1993 Aug;47(1):23-34 PMID: 8376546
  51. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130.
    Science. 1994 Jan 7;263(5143):89-92 PMID: 8272872
  52. T and B memory cells.
    Cell. 1994 Jan 28;76(2):315-22 PMID: 8293465
  53. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.
    Science. 1994 Apr 1;264(5155):95-8 PMID: 8140422
  54. Turnover of naive- and memory-phenotype T cells.
    J Exp Med. 1994 Apr 1;179(4):1127-35 PMID: 8145034
  55. Transcriptional activation of the IL-6 response element in the junB promoter is mediated by multiple Stat family proteins.
    Biochem Biophys Res Commun. 1994 Jul 29;202(2):1181-7 PMID: 7519422
  56. Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily.
    Stem Cells. 1994 May;12(3):262-77 PMID: 8075593
  57. Interleukin-6 signaling via four transcription factors binding palindromic enhancers of different genes.
    J Biol Chem. 1994 Oct 21;269(42):26191-5 PMID: 7523403
  58. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95)
    Nature. 1995 Feb 2;373(6513):438-41 PMID: 7530335
  59. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice.
    Immunity. 1994 Aug;1(5):365-71 PMID: 7533645
  60. Lipopolysaccharide interferes with the induction of peripheral T cell death.
    Immunity. 1995 Mar;2(3):261-70 PMID: 7535182
  61. Requirement of serine phosphorylation for formation of STAT-promoter complexes.
    Science. 1995 Mar 31;267(5206):1990-4 PMID: 7701321
  62. Costimulation with B7-1, IL-6, and IL-12 is sufficient for primary generation of murine antitumor cytolytic T lymphocytes in vitro.
    J Immunol. 1995 Jun 1;154(11):5637-48 PMID: 7538528
  63. Growth factors can enhance lymphocyte survival without committing the cell to undergo cell division.
    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5491-5 PMID: 7777536
  64. The survival and turnover of mature and immature CD8 T cells.
    Immunology. 1995 Apr;84(4):514-20 PMID: 7790023
  65. Regulation of lymphocyte survival by the bcl-2 gene family.
    Annu Rev Immunol. 1995;13:513-43 PMID: 7612233
  66. Life span of naive and memory T cells.
    Stem Cells. 1995 May;13(3):242-9 PMID: 7613491
  67. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL.
    Immunity. 1995 Jul;3(1):87-98 PMID: 7621080
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.191.6.915
Published
2000-03-20
Pages
915-26
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193120
Subset
IM
Grants
NIAID NIH HHS · AI22295 · United States
NIAID NIH HHS · AI18785 · United States
NIAID NIH HHS · AI17134 · United States
External Links
PubMed source DOI: 10.1084/jem.191.6.915 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2