Home LiteratureArticle Details
PMID: 9892606 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc.

The Journal of experimental medicine ·Vol. 189 ·No. 2 ·1999-01-18 ·Pages 231-9

Genestier L, Kasibhatla S, Brunner T, Green DR

Abstract

Activation-induced cell death (AICD) is a process that regulates the size and the duration of the primary immune T cell response. In this report, we investigated the mechanisms involved in the regulation of AICD by transforming growth factor beta1 (TGF-beta1). We found that TGF-beta1 decreased apoptosis of human T cells or T cell hybridomas after activation by anti-CD3. This decrease was associated with inhibition of Fas (Apo-1/CD95) ligand (FasL) expression, whereas Fas signaling was not affected by TGF-beta1. In parallel, TGF-beta1 inhibited c-Myc expression in T cell hybridomas, and ectopic expression of a chimeric molecule composed of c-Myc and the steroid binding domain of the estrogen receptor (Myc-ER) blocked both the inhibition of FasL and the decrease of AICD induced by TGF-beta1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-beta1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses.

MeSH Terms
Animals Apoptosis/drug effects CD3 Complex/immunology Cell Cycle/drug effects DNA Fragmentation/drug effects,genetics Down-Regulation/drug effects Fas Ligand Protein Gene Expression Regulation/genetics Hybridomas/drug effects Membrane Glycoproteins/genetics Mice Proto-Oncogene Proteins c-myc/genetics RNA, Messenger/genetics Receptors, Estrogen/genetics Recombinant Fusion Proteins/genetics T-Lymphocytes/drug effects Tamoxifen/analogs & derivatives,pharmacology Transforming Growth Factor beta/pharmacology
Chemicals
CD3 Complex FASLG protein, human Fas Ligand Protein Fasl protein, mouse Membrane Glycoproteins Proto-Oncogene Proteins c-myc RNA, Messenger Receptors, Estrogen Recombinant Fusion Proteins Transforming Growth Factor beta Tamoxifen afimoxifene
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Genestier L
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Kasibhatla S
Brunner T
Green D R
References (58)
58 references, click to expand
  1. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas.
    Science. 1992 Jul 10;257(5067):212-4 PMID: 1378649
  2. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.
    Nature. 1992 Oct 22;359(6397):693-9 PMID: 1436033
  3. Induction of apoptosis in fibroblasts by c-myc protein.
    Cell. 1992 Apr 3;69(1):119-28 PMID: 1555236
  4. Immunomodulatory effects of transforming growth factor-beta on T lymphocytes. Induction of CD8 expression in the CTLL-2 cell line and in normal thymocytes.
    J Immunol. 1992 Jun 15;148(12):3847-56 PMID: 1602133
  5. Anti-immunoglobulin treatment of murine B-cell lymphomas induces active transforming growth factor beta but pRB hypophosphorylation is transforming growth factor beta independent.
    Cell Growth Differ. 1992 Mar;3(3):175-81 PMID: 1633108
  6. Transforming growth factor-beta and IL-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype.
    J Immunol. 1991 Nov 1;147(9):2991-3000 PMID: 1680924
  7. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry.
    J Immunol Methods. 1991 Jun 3;139(2):271-9 PMID: 1710634
  8. Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1.
    J Immunol. 1991 Sep 15;147(6):1792-6 PMID: 1716279
  9. Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta.
    J Immunol. 1991 May 15;146(10):3289-97 PMID: 1827481
  10. Co-stimulation of T cell proliferation by transforming growth factor-beta 1.
    J Immunol. 1991 Aug 15;147(4):1127-33 PMID: 1831218
  11. T cell memory is short-lived in the absence of antigen.
    J Exp Med. 1991 Nov 1;174(5):969-74 PMID: 1834764
  12. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice.
    Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2918-21 PMID: 2011600
  13. TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains.
    Cell. 1990 Jun 1;61(5):777-85 PMID: 2140528
  14. The transforming growth factor-beta family.
    Annu Rev Cell Biol. 1990;6:597-641 PMID: 2177343
  15. Is T-cell memory maintained by crossreactive stimulation?
    Immunol Today. 1990 Jun;11(6):203-5 PMID: 2191683
  16. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights.
    Cell. 1990 Oct 19;63(2):245-7 PMID: 2208284
  17. New light on Myc and Myb. Part I. Myc.
    Genes Dev. 1990 Dec;4(12A):2025-35 PMID: 2269425
  18. Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression.
    J Immunol. 1990 Mar 1;144(5):1767-76 PMID: 2407783
  19. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta.
    Mol Cell Biol. 1988 Aug;8(8):3088-93 PMID: 2463471
  20. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells.
    Nature. 1989 Jul 6;340(6228):66-8 PMID: 2662015
  21. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes.
    Nature. 1989 Jun 22;339(6226):625-6 PMID: 2786609
  22. Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2.
    J Immunol. 1989 Nov 15;143(10):3222-9 PMID: 2809198
  23. Transforming growth factor-beta inhibits the generation of cytotoxic T cells in virus-infected mice.
    J Immunol. 1989 Nov 15;143(10):3230-4 PMID: 2809199
  24. Effects of transforming growth factor-beta on human lymphokine-activated killer cell precursors. Autocrine inhibition of cellular proliferation and differentiation to immune killer cells.
    J Immunol. 1988 Jul 15;141(2):690-8 PMID: 3133414
  25. Cell growth cycle block of T cell hybridomas upon activation with antigen.
    J Exp Med. 1987 Jan 1;165(1):173-94 PMID: 3491868
  26. Fas ligand mediates activation-induced cell death in human T lymphocytes.
    J Exp Med. 1995 Jan 1;181(1):71-7 PMID: 7528780
  27. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95)
    Nature. 1995 Feb 2;373(6513):438-41 PMID: 7530335
  28. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas.
    Nature. 1995 Feb 2;373(6513):441-4 PMID: 7530336
  29. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation.
    Nature. 1995 Feb 2;373(6513):444-8 PMID: 7530337
  30. Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids.
    J Exp Med. 1995 May 1;181(5):1673-82 PMID: 7536793
  31. 9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation.
    Mol Cell Biol. 1995 Oct;15(10):5576-85 PMID: 7565709
  32. Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion.
    J Exp Med. 1995 Sep 1;182(3):699-709 PMID: 7650478
  33. Production of high-titer helper-free retroviruses by transient transfection.
    Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392-6 PMID: 7690960
  34. Promotion and inhibition of activation-induced apoptosis in T-cell hybridomas by oncogenes and related signals.
    Immunol Rev. 1994 Dec;142:321-42 PMID: 7698799
  35. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins.
    Nucleic Acids Res. 1995 May 25;23(10):1686-90 PMID: 7784172
  36. Functional Myc-Max heterodimer is required for activation-induced apoptosis in T cell hybridomas.
    J Exp Med. 1994 Dec 1;180(6):2413-8 PMID: 7964516
  37. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.
    Nature. 1994 Sep 15;371(6494):257-61 PMID: 8078588
  38. Signaling properties of anti-immunoglobulin--resistant variants of WEHI-231 B lymphoma cells.
    Eur J Immunol. 1994 Sep;24(9):1993-9 PMID: 8088319
  39. Lymphoma models for B cell activation and tolerance. X. Anti-mu-mediated growth arrest and apoptosis of murine B cell lymphomas is prevented by the stabilization of myc.
    J Exp Med. 1994 Jan 1;179(1):221-8 PMID: 8270867
  40. Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle.
    Eur J Immunol. 1993 Jul;23(7):1552-60 PMID: 8325332
  41. Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor.
    J Immunol. 1993 Jul 15;151(2):1116-27 PMID: 8335893
  42. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest.
    Cell. 1993 Sep 24;74(6):1009-20 PMID: 8402878
  43. Fas- and activation-induced apoptosis are reduced in human T cells preactivated in the presence of TGF-beta 1.
    J Immunol. 1996 Jan 15;156(2):459-64 PMID: 8543794
  44. Fas and FasL in the homeostatic regulation of immune responses.
    Immunol Today. 1995 Dec;16(12):569-74 PMID: 8579749
  45. Cdc25 cell-cycle phosphatase as a target of c-myc.
    Nature. 1996 Aug 8;382(6591):511-7 PMID: 8700224
  46. Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells.
    Mol Cell Biol. 1996 Sep;16(9):5015-25 PMID: 8756660
  47. Activation-induced cell death in murine T cell hybridomas. Differential regulation of Fas (CD95) versus Fas ligand expression by cyclosporin A and FK506.
    Int Immunol. 1996 Jul;8(7):1017-26 PMID: 8757947
  48. TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha.
    Immunity. 1996 Jul;5(1):31-40 PMID: 8758892
  49. Role of alpha 5 beta 1 integrin in TGF-beta 1-costimulated CD8+ T cell growth and apoptosis.
    J Immunol. 1996 Oct 1;157(7):2916-23 PMID: 8816397
  50. TGF-beta 1 promotes in vitro generation of dendritic cells by protecting progenitor cells from apoptosis.
    J Immunol. 1997 Feb 15;158(4):1591-7 PMID: 9029094
  51. Down-modulation of c-myc expression induces apoptosis of B lymphocyte models of tolerance via clonal deletion.
    J Immunol. 1997 Mar 1;158(5):1994-7 PMID: 9036941
  52. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15.
    Nature. 1997 May 22;387(6631):417-22 PMID: 9163429
  53. TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes.
    J Immunol. 1997 Jul 1;159(1):175-83 PMID: 9200453
  54. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis.
    Science. 1997 Nov 14;278(5341):1305-9 PMID: 9360929
  55. Dominant negative mutants of TRAF3 reveal an important role for the coiled coil domains in cell death signaling by the lymphotoxin-beta receptor.
    J Biol Chem. 1997 Dec 5;272(49):30835-40 PMID: 9388227
  56. Two NFAT transcription factor binding sites participate in the regulation of CD95 (Fas) ligand expression in activated human T cells.
    J Biol Chem. 1997 Dec 12;272(50):31427-34 PMID: 9395475
  57. Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappaB activation.
    EMBO J. 1997 Dec 15;16(24):7382-92 PMID: 9405367
  58. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity.
    J Exp Med. 1998 Apr 20;187(8):1205-13 PMID: 9547332
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.189.2.231
Published
1999-01-18
Pages
231-9
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2192981
Subset
IM
Grants
NIGMS NIH HHS · GM52735 · United States
External Links
PubMed source DOI: 10.1084/jem.189.2.231 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