Home LiteratureArticle Details
PMID: 19604493 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo.

Immunity ·Vol. 31 ·No. 1 ·2009-07-17 ·Pages 145-57

Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI

Abstract

Although deficient CD8(+) T cell responses have long been associated with chronic viral infections, the underlying mechanisms are still unclear. Here we report that sustained transforming growth factor-beta (TGF-beta) expression and phosphorylation of its signaling mediator, Smad-2, were distinctive features of virus-specific CD8(+) T cells during chronic versus acute viral infections in vivo. The result was TGF-beta-dependent apoptosis of virus-specific CD8(+) T cells that related to upregulation of the proapoptotic protein Bim during chronic infection. Moreover, selective attenuation of TGF-beta signaling in T cells increased the numbers and multiple functions of antiviral CD8(+) T cells and enabled rapid eradication of the persistence-prone virus and memory generation. Finally, we found that cell-intrinsic TGF-beta signaling was responsible for virus-specific-CD8(+) T cell apoptosis and decreased numbers but was not necessary for their functional exhaustion. Our findings reveal persisting TGF-beta-Smad signaling as a hallmark and key regulator of CD8(+) T cell responses during chronic viral infections in vivo.

MeSH Terms
Adoptive Transfer Animals Apoptosis/immunology Apoptosis Regulatory Proteins/immunology,metabolism Arenaviridae Infections/immunology,virology Bcl-2-Like Protein 11 CD8-Positive T-Lymphocytes/immunology,metabolism Lymphocyte Depletion Lymphocytic choriomeningitis virus/immunology Membrane Proteins/immunology,metabolism Mice Mice, Inbred C57BL Phosphorylation/immunology Proto-Oncogene Proteins/immunology,metabolism Signal Transduction/immunology Smad2 Protein/immunology,metabolism Transforming Growth Factor beta/immunology,metabolism
Chemicals
Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Membrane Proteins Proto-Oncogene Proteins Smad2 Protein Smad2 protein, mouse Transforming Growth Factor beta
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tinoco Roberto
Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093-0322, USA.
Alcalde Victor
Yang Yating
Sauer Karsten
Zuniga Elina I
References (68)
68 references, click to expand
  1. T cells and viral persistence: lessons from diverse infections.
    Nat Immunol. 2005 Sep;6(9):873-9 PMID: 16116467
  2. Resolution of a chronic viral infection after interleukin-10 receptor blockade.
    J Exp Med. 2006 Oct 30;203(11):2461-72 PMID: 17030951
  3. Transforming growth factor-beta expression and natural killer cell responses during virus infection of normal, nude, and SCID mice.
    J Immunol. 1993 Nov 1;151(9):4874-90 PMID: 8409446
  4. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion.
    J Virol. 2006 Nov;80(22):11398-403 PMID: 16956940
  5. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus.
    J Clin Invest. 1994 Feb;93(2):768-75 PMID: 8113410
  6. TGFbeta in Cancer.
    Cell. 2008 Jul 25;134(2):215-30 PMID: 18662538
  7. A role for transforming growth factor-beta 1 in regulating natural killer cell and T lymphocyte proliferative responses during acute infection with lymphocytic choriomeningitis virus.
    J Immunol. 1991 Oct 15;147(8):2717-27 PMID: 1918986
  8. Making sense of latent TGFbeta activation.
    J Cell Sci. 2003 Jan 15;116(Pt 2):217-24 PMID: 12482908
  9. Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression.
    J Virol. 1995 Feb;69(2):1059-70 PMID: 7815484
  10. Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia.
    Cancer Cell. 2007 Oct;12(4):313-27 PMID: 17936557
  11. Restoring function in exhausted CD8 T cells during chronic viral infection.
    Nature. 2006 Feb 9;439(7077):682-7 PMID: 16382236
  12. NF-AT-mediated expression of TGF-beta1 in tolerant T cells.
    J Immunol. 2007 Mar 1;178(5):3067-75 PMID: 17312153
  13. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.
    Nat Immunol. 2009 Jan;10(1):29-37 PMID: 19043418
  14. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses.
    J Virol. 2007 Jun;81(11):5882-92 PMID: 17376924
  15. Endocrine expression of the active form of TGF-beta1 in the TGF-beta1 null mice fails to ameliorate lethal phenotype.
    Cytokine. 2002 Apr 7;18(1):43-50 PMID: 12090759
  16. Multiple-cytokine-producing antiviral CD4 T cells are functionally superior to single-cytokine-producing cells.
    J Virol. 2007 Aug;81(16):8468-76 PMID: 17553885
  17. 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
  18. Immunopathogenesis and immunotherapy in AIDS virus infections.
    Nat Med. 2003 Jul;9(7):861-6 PMID: 12835706
  19. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.
    Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15430-5 PMID: 17878315
  20. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
    Cell. 2003 Jun 13;113(6):685-700 PMID: 12809600
  21. TGF-beta in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus.
    Cell Death Differ. 2007 Oct;14(10):1747-58 PMID: 17612589
  22. Viral immune evasion due to persistence of activated T cells without effector function.
    J Exp Med. 1998 Dec 21;188(12):2205-13 PMID: 9858507
  23. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells.
    Nature. 1993 Apr 22;362(6422):758-61 PMID: 8469287
  24. Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections.
    Cell Host Microbe. 2008 Oct 16;4(4):374-86 PMID: 18854241
  25. TGFbeta signalling in control of T-cell-mediated self-reactivity.
    Nat Rev Immunol. 2007 Jun;7(6):443-53 PMID: 17525753
  26. T-cell quality in memory and protection: implications for vaccine design.
    Nat Rev Immunol. 2008 Apr;8(4):247-58 PMID: 18323851
  27. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection.
    J Exp Med. 2006 Oct 2;203(10):2281-92 PMID: 16954372
  28. Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus.
    J Virol. 1993 Dec;67(12):7340-9 PMID: 7693969
  29. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.
    J Virol. 2007 Apr;81(8):4215-25 PMID: 17287266
  30. Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells.
    J Virol. 2001 Sep;75(18):8407-23 PMID: 11507186
  31. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.
    J Exp Med. 1986 May 1;163(5):1037-50 PMID: 2871125
  32. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
    Nature. 2006 Sep 21;443(7109):350-4 PMID: 16921384
  33. Persistent numbers of tetramer+ CD8(+) T cells, but loss of interferon-gamma+ HIV-specific T cells during progression to AIDS.
    Blood. 2002 Apr 1;99(7):2505-11 PMID: 11895786
  34. Molecular signature of CD8+ T cell exhaustion during chronic viral infection.
    Immunity. 2007 Oct;27(4):670-84 PMID: 17950003
  35. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
    Nat Med. 2006 Oct;12(10):1198-202 PMID: 16917489
  36. T cells doing it for themselves: TGF-beta regulation of Th1 and Th17 cells.
    Immunity. 2007 May;26(5):547-9 PMID: 17521582
  37. Enhancing SIV-specific immunity in vivo by PD-1 blockade.
    Nature. 2009 Mar 12;458(7235):206-10 PMID: 19078956
  38. Interleukin-10 determines viral clearance or persistence in vivo.
    Nat Med. 2006 Nov;12(11):1301-9 PMID: 17041596
  39. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.
    J Virol. 2003 Apr;77(8):4911-27 PMID: 12663797
  40. TGF-beta in the cardiovascular system: molecular mechanisms of a context-specific growth factor.
    Trends Cardiovasc Med. 2000 Apr;10(3):132-7 PMID: 11428000
  41. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors.
    Blood. 2007 Jun 1;109(11):4671-8 PMID: 17272504
  42. Role of Bim in regulating CD8+ T-cell responses during chronic viral infection.
    J Virol. 2006 Sep;80(17):8627-38 PMID: 16912311
  43. Blocking of interleukin-10 receptor--a novel approach to stimulate T-helper cell type 1 responses to hepatitis C virus.
    Clin Immunol. 2005 Oct;117(1):57-64 PMID: 16006191
  44. CD8 T cell dysfunction during chronic viral infection.
    Curr Opin Immunol. 2007 Aug;19(4):408-15 PMID: 17656078
  45. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease.
    Immunity. 2000 Feb;12(2):171-81 PMID: 10714683
  46. The role of proteases in transforming growth factor-beta activation.
    Int J Biochem Cell Biol. 2008;40(6-7):1068-78 PMID: 18243766
  47. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms.
    Immunity. 2006 Sep;25(3):455-71 PMID: 16973386
  48. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770-4 PMID: 8421714
  49. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection.
    Science. 2009 Mar 27;323(5922):1726-9 PMID: 19325114
  50. Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship.
    Eur J Cell Biol. 2008 Sep;87(8-9):601-15 PMID: 18342983
  51. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.
    Blood. 2006 Jun 15;107(12):4781-9 PMID: 16467198
  52. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus.
    J Virol. 2001 Jun;75(12):5550-8 PMID: 11356962
  53. Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion.
    J Immunol. 2009 Jun 1;182(11):6697-708 PMID: 19454664
  54. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor.
    Immunity. 2006 Sep;25(3):441-54 PMID: 16973387
  55. T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses.
    J Virol. 1988 Jun;62(6):2102-6 PMID: 2966865
  56. HIV antigens can induce TGF-beta(1)-producing immunoregulatory CD8+ T cells.
    J Immunol. 2002 Mar 1;168(5):2247-54 PMID: 11859112
  57. Infection of dendritic cells by lymphocytic choriomeningitis virus.
    Curr Top Microbiol Immunol. 2003;276:125-44 PMID: 12797446
  58. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence.
    J Exp Med. 1984 Aug 1;160(2):521-40 PMID: 6332167
  59. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity.
    Immunity. 2008 Feb;28(2):197-205 PMID: 18275830
  60. Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection.
    Nat Immunol. 2004 Dec;5(12):1227-34 PMID: 15531885
  61. Immunology of hepatitis B virus and hepatitis C virus infection.
    Nat Rev Immunol. 2005 Mar;5(3):215-29 PMID: 15738952
  62. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection.
    Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20428-33 PMID: 19075244
  63. Impaired function of circulating HIV-specific CD8(+) T cells in chronic human immunodeficiency virus infection.
    Blood. 2000 Nov 1;96(9):3094-101 PMID: 11049989
  64. Transforming growth factor-beta regulation of immune responses.
    Annu Rev Immunol. 2006;24:99-146 PMID: 16551245
  65. High antigen levels are the cause of T cell exhaustion during chronic viral infection.
    Proc Natl Acad Sci U S A. 2009 May 26;106(21):8623-8 PMID: 19433785
  66. Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution.
    Development. 2000 Jul;127(14):3107-18 PMID: 10862748
  67. In vitro restoration of T cell immune function in human immunodeficiency virus-positive persons: effects of interleukin (IL)-12 and anti-IL-10.
    J Infect Dis. 1996 May;173(5):1085-91 PMID: 8627058
  68. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression.
    J Virol. 2007 Mar;81(6):2545-53 PMID: 17182670
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2009.06.015
Published
2009-07-17
Pages
145-57
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3039716
Subset
IM
Grants
NIAID NIH HHS · R21 AI072752 · United States
NIAID NIH HHS · AI081923 · United States
NIAID NIH HHS · R01 AI009484 · United States
NIAID NIH HHS · R01 AI081923 · United States
NIAID NIH HHS · AI070845 · United States
NIAID NIH HHS · R01 AI070845 · United States
NIAID NIH HHS · AI45927 · United States
NIAID NIH HHS · AI072752 · United States
NIAID NIH HHS · R01 AI045927 · United States
NIAID NIH HHS · R01 AI081923-01A1 · United States
NIAID NIH HHS · R21 AI072752-01A2 · United States
NIAID NIH HHS · AI09484 · United States
External Links
PubMed source DOI: 10.1016/j.immuni.2009.06.015 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