Skip to main content

Advertisement

SpringerLink
Log in

Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

We have recently provided data suggesting a potential role for mitochondria and Bcl-2-family molecules in apoptosis sensitivity of HIV-specific CD8+ T cells. Here, we report on the role of filamentous (F) actin in this process. Disruption of actin by cytochalasin D (cytD) or lantrunculin A remarkably reduced CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells while their spontaneous apoptosis was unaffected. This inhibition cannot be attributed to changes of CD95/Fas distribution or levels in these cells. Furthermore, cytD treatment reduced CD95/Fas-induced apoptosis of CD8+ T cells from HIV+ patients independently of their differentiation status. CD95/Fas-induced apoptosis of both CD38+ and CD38− HIV-specific CD8+ T cells was inhibited by cytD treatment indicating that actin mediates this apoptotic process independently of the activation level of these cells. CytD was found to reduce the activation of caspase-8 induced by short treatment of purified CD8+ T cells from HIV+ patients with anti-CD95/Fas. Our data reveal actin as a critical mediator of HIV-specific CD8+ T cell apoptosis; further analysis of the molecular mechanisms governing this process may potentially contribute to design new therapies targeting the enhancement of the immune system in HIV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gougeon ML (2003) Apoptosis as an HIV strategy to escape immune attack. Nat Rev Immunol 3(5):392–404

    Article  PubMed  CAS  Google Scholar 

  2. Chun TN, Justement JS, Sanford C et al (2004) Relationship between the frequency of HIV-specific CD8+ T cells and the level of CD38+CD8+ T cells in untreated HIV-infected individuals. Proc Natl Acad Sci USA 101(8):2464–2469

    Article  PubMed  CAS  Google Scholar 

  3. Petrovas C, Mueller YM, Katsikis PD (2005) Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy. Cell Death Differ 12(Suppl 1):859–870

    Article  PubMed  CAS  Google Scholar 

  4. Mueller YM, De Rosa SC, Hutton JA et al (2001) Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells. Immunity 15(6):871–882

    Article  PubMed  CAS  Google Scholar 

  5. Selliah N, Finkel TH (2001) Biochemical mechanisms of HIV induced T cell apoptosis. Cell Death Differ 8(2):127–136

    Article  PubMed  CAS  Google Scholar 

  6. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281(5381):1312–1316

    Article  PubMed  CAS  Google Scholar 

  7. Thome M, Tschopp J (2001) Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol 1(1):50–58

    Article  PubMed  CAS  Google Scholar 

  8. Barnhart BC, Alappat EC, Peter ME (2003) The CD95 type I/type II model. Semin Immunol 15(3):185–193

    Article  PubMed  CAS  Google Scholar 

  9. Algeciras-Schimnich A, Shen L, Barnhart BC, Murmann AE, Burkhardt JK, Peter ME (2002) Molecular ordering of the initial signaling events of CD95. Mol Cell Biol 22(1):207–220

    Article  PubMed  CAS  Google Scholar 

  10. Scaffidi C, Fulda S, Srinivasan A et al (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17(6):1675–1687

    Article  PubMed  CAS  Google Scholar 

  11. Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME (1999) Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274(32):22532–22538

    Article  PubMed  CAS  Google Scholar 

  12. Strasser A, Harris AW, Huang DC, Krammer PH, Cory S (1995) Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J 14(24):6136–6147

    PubMed  CAS  Google Scholar 

  13. Huang DC, Hahne M, Schroeter M et al (1999) Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x(L). Proc Natl Acad Sci USA 96(26):14871–14876

    Article  PubMed  CAS  Google Scholar 

  14. Gulbins E, Bissonnette R, Mahboubi A, et al (1995) FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 2(4):341–351

    Article  PubMed  CAS  Google Scholar 

  15. Alam MK, Davison S, Siddiqui N, Norton JD, Murphy JJ (1997) Ectopic expression of Bcl-2, but not Bcl-xL rescues Ramos B cells from Fas-mediated apoptosis. Eur J Immunol 27(12):3485–3491

    Article  PubMed  CAS  Google Scholar 

  16. Sun XM, Bratton SB, Butterworth M, MacFarlane M, Cohen GM (2002) Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mitochondrial release of Smac/DIABLO and subsequent inactivation of X-linked inhibitor-of-apoptosis protein. J Biol Chem 277(13):11345–11351

    Article  PubMed  CAS  Google Scholar 

  17. Peter ME, Kischkel FC, Scheuerpflug SG, Medema JP, Debatin KM, Krammer PH (1997) Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex. Eur J Immunol 27(5):1207–1212

    Article  PubMed  CAS  Google Scholar 

  18. Celeste Morley S, Sun GP, Bierer BE (2003) Inhibition of actin polymerization enhances commitment to and execution of apoptosis induced by withdrawal of trophic support. J Cell Biochem 88(5):1066–1076

    Article  PubMed  CAS  Google Scholar 

  19. Luciani F, Matarrese P, Giammarioli AM et al (2004) CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4(+)T lymphocytes. Cell Death Differ 11(5):574–582

    Article  PubMed  CAS  Google Scholar 

  20. Gajate C, Mollinedo F (2005) Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J Biol Chem 280(12):11641–11647

    Article  PubMed  CAS  Google Scholar 

  21. Fais S, De Milito A, Lozupone F (2005) The role of FAS to ezrin association in FAS-mediated apoptosis. Apoptosis 10(5):941–947

    Article  PubMed  CAS  Google Scholar 

  22. Parlato S, Giammarioli AM, Logozzi M et al (2000) CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway. EMBO J 19(19):5123–5134

    Article  PubMed  CAS  Google Scholar 

  23. Westendorp MO, Frank R, Ochsenbauer C et al (1995) Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375(6531):497–500

    Article  PubMed  CAS  Google Scholar 

  24. Petrovas C, Mueller YM, Dimitriou ID et al (2006) Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells. Blood 109(6): 2505–2513

    Article  PubMed  Google Scholar 

  25. Petrovas C, Mueller YM, Dimitriou ID et al (2004) HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. J Immunol 172(7):4444–4453

    PubMed  CAS  Google Scholar 

  26. Altman JD, Moss PA, Goulder PG et al (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274(5284):94–96

    Article  PubMed  CAS  Google Scholar 

  27. Drake DR, Braciale TJ 3rd (2001) Cutting edge: lipid raft integrity affects the efficiency of MHC class I tetramer binding and cell surface TCR arrangement on CD8+ T cells. J Immunol 166(12):7009–7013

    PubMed  CAS  Google Scholar 

  28. Ayscough KR, Stryker J, Pokala N, Sanders M, Crews P, Drubin DG (1997) High rates of actin filament turnover in budding yeast and roles for actin in establishment and maintenance of cell polarity revealed using the actin inhibitor latrunculin-A. J Cell Biol 137(2):399–416

    Article  PubMed  CAS  Google Scholar 

  29. Charrin S, Alcover A (2006) Role of ERM (ezrin-radixin-moesin) proteins in T lymphocyte polarization, immune synapse formation and in T cell receptor-mediated signaling. Front Biosci 11:1987–1997

    Article  PubMed  CAS  Google Scholar 

  30. de Oliveira Pinto LM, Garcia S, Lecoeur H, Rapp C, Gougeon ML (2002) Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood 99(5):1666–1675

    Article  PubMed  Google Scholar 

  31. Soderstrom TS, Nyberg SD, Eriksson JE (2005) CD95 capping is ROCK-dependent and dispensable for apoptosis. J Cell Sci 118(Pt 10):2211–2223

    Article  PubMed  Google Scholar 

  32. Ailenberg M, Silverman M (2003) Cytochalasin D disruption of actin filaments in 3T3 cells produces an anti-apoptotic response by activating gelatinase A extracellularly and initiating intracellular survival signals. Biochim Biophys Acta 1593(2–3):249–258

    PubMed  CAS  Google Scholar 

  33. Rivas FV, O’Keefe JP, Alegre ML, Gajewski TF (2004) Actin cytoskeleton regulates calcium dynamics and NFAT nuclear duration. Mol Cell Biol 24(4):1628–1639

    Article  PubMed  CAS  Google Scholar 

  34. Krishnan S, Nambiar MP, Warke VG et al (2004) Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J Immunol 172(12):7821–7831

    PubMed  CAS  Google Scholar 

  35. Fluur C, De Milito A, Fry TJ et al (2007) Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J Immunol 178(8):5340–5350

    PubMed  CAS  Google Scholar 

  36. Lee KH, Feig C, Tchikov V et al (2006) The role of receptor internalization in CD95 signaling. EMBO J 25(5):1009–1023

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the staff of the Partnership Comprehensive Care Practice of the HIV/AIDS Medicine Division of Drexel University College of Medicine for patient recruitment. The authors have no conflicting financial interests.

This work was supported in part by National Institutes of Health grants R01 AI46719 and R01 AI52005 to P.D.K.

Author information

Author notes

  1. Constantinos Petrovas

    Present address: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA

Authors and Affiliations

  1. Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Drexel University, 2900 Queen Lane, Philadelphia, PA, 19129, USA

    Constantinos Petrovas, Yvonne M. Mueller, Guibin Yang, Susan R. Altork & Peter D. Katsikis

  2. Department of Medicine, Drexel University College of Medicine, Drexel University, Philadelphia, PA, 19129, USA

    Jeffrey M. Jacobson & Peter G. Pitsakis

  3. Philadelphia FIGHT, Philadelphia, PA, 19107, USA

    Karam C. Mounzer

  4. Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30329, USA

    John D. Altman

Authors
  1. Constantinos Petrovas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvonne M. Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guibin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan R. Altork
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey M. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter G. Pitsakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karam C. Mounzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John D. Altman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter D. Katsikis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter D. Katsikis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petrovas, C., Mueller, Y.M., Yang, G. et al. Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells. Apoptosis 12, 2175–2186 (2007). https://doi.org/10.1007/s10495-007-0128-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-007-0128-y

Keywords

Search

Navigation