Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Jun 1;181(6):2029–2036. doi: 10.1084/jem.181.6.2029

Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals

PMCID: PMC2192074  PMID: 7539037

Abstract

Apoptosis (programmed cell death) of T lymphocytes has been proposed as a mechanism which plays an important role in the pathogenesis of human immunodeficiency virus (HIV) disease. Activation of Fas (CD95) can either result in costimulation of proliferation and cytokine production or in the induction of apoptosis of T lymphocytes. This raises the possibility that Fas is involved in the observed T cell apoptosis during HIV disease. In this report we show that peripheral blood CD4+ and CD8+ T lymphocytes from HIV-infected individuals undergo apoptosis in vitro in response to antibody stimulation (cross-linking) of Fas at a much higher frequency than from uninfected controls. This anti-Fas- induced T cell apoptosis is markedly higher than spontaneous T cell apoptosis in HIV-infected individuals. Antibodies against other members of the tumor necrosis factor (TNF)/nerve growth factor receptor family such as CD27, CD30, CD40, 4-1BB, p55 TNF receptor, p75 TNF receptor, and TNF receptor-related protein did not result in any increase of T cell apoptosis above that spontaneously observed in HIV+ individuals. Anti-Fas-induced apoptosis was much higher in symptomatic HIV-infected individuals; and the magnitude of anti-Fas-induced CD4+ T cell apoptosis correlated inversely with peripheral blood CD4+ T cell absolute counts. Surface expression of Fas on T cells was also found to be higher in HIV-infected individuals. Resting and activated CD4+ and CD8+ T cells both underwent apoptosis in response to anti-Fas antibody. L-Selectin positive memory CD4+ T cells were especially susceptible to anti-Fas-induced apoptosis. These findings show that CD4+ and CD8+ T lymphocytes in HIV-infected individuals are primed in vivo to undergo apoptosis in response to Fas stimulation, suggesting that Fas signaling may be responsible for the T lymphocyte functional defects and depletion observed in HIV disease.

Full Text

The Full Text of this article is available as a PDF (883.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderson M. R., Armitage R. J., Maraskovsky E., Tough T. W., Roux E., Schooley K., Ramsdell F., Lynch D. H. Fas transduces activation signals in normal human T lymphocytes. J Exp Med. 1993 Dec 1;178(6):2231–2235. doi: 10.1084/jem.178.6.2231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alderson M. R., Smith C. A., Tough T. W., Davis-Smith T., Armitage R. J., Falk B., Roux E., Baker E., Sutherland G. R., Din W. S. Molecular and biological characterization of human 4-1BB and its ligand. Eur J Immunol. 1994 Sep;24(9):2219–2227. doi: 10.1002/eji.1830240943. [DOI] [PubMed] [Google Scholar]
  3. Banda N. K., Bernier J., Kurahara D. K., Kurrle R., Haigwood N., Sekaly R. P., Finkel T. H. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med. 1992 Oct 1;176(4):1099–1106. doi: 10.1084/jem.176.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonyhadi M. L., Rabin L., Salimi S., Brown D. A., Kosek J., McCune J. M., Kaneshima H. HIV induces thymus depletion in vivo. Nature. 1993 Jun 24;363(6431):728–732. doi: 10.1038/363728a0. [DOI] [PubMed] [Google Scholar]
  5. Callebaut C., Krust B., Jacotot E., Hovanessian A. G. T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Science. 1993 Dec 24;262(5142):2045–2050. doi: 10.1126/science.7903479. [DOI] [PubMed] [Google Scholar]
  6. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dive C., Gregory C. D., Phipps D. J., Evans D. L., Milner A. E., Wyllie A. H. Analysis and discrimination of necrosis and apoptosis (programmed cell death) by multiparameter flow cytometry. Biochim Biophys Acta. 1992 Feb 3;1133(3):275–285. doi: 10.1016/0167-4889(92)90048-g. [DOI] [PubMed] [Google Scholar]
  8. Estaquier J., Idziorek T., de Bels F., Barré-Sinoussi F., Hurtrel B., Aubertin A. M., Venet A., Mehtali M., Muchmore E., Michel P. Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9431–9435. doi: 10.1073/pnas.91.20.9431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
  10. Groux H., Torpier G., Monté D., Mouton Y., Capron A., Ameisen J. C. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. doi: 10.1084/jem.175.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gutheil W. G., Subramanyam M., Flentke G. R., Sanford D. G., Munoz E., Huber B. T., Bachovchin W. W. Human immunodeficiency virus 1 Tat binds to dipeptidyl aminopeptidase IV (CD26): a possible mechanism for Tat's immunosuppressive activity. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6594–6598. doi: 10.1073/pnas.91.14.6594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hanabuchi S., Koyanagi M., Kawasaki A., Shinohara N., Matsuzawa A., Nishimura Y., Kobayashi Y., Yonehara S., Yagita H., Okumura K. Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4930–4934. doi: 10.1073/pnas.91.11.4930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  14. Kobayashi N., Hamamoto Y., Yamamoto N., Ishii A., Yonehara M., Yonehara S. Anti-Fas monoclonal antibody is cytocidal to human immunodeficiency virus-infected cells without augmenting viral replication. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9620–9624. doi: 10.1073/pnas.87.24.9620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kägi D., Vignaux F., Ledermann B., Bürki K., Depraetere V., Nagata S., Hengartner H., Golstein P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994 Jul 22;265(5171):528–530. doi: 10.1126/science.7518614. [DOI] [PubMed] [Google Scholar]
  16. Lowin B., Hahne M., Mattmann C., Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature. 1994 Aug 25;370(6491):650–652. doi: 10.1038/370650a0. [DOI] [PubMed] [Google Scholar]
  17. Lu Y. Y., Koga Y., Tanaka K., Sasaki M., Kimura G., Nomoto K. Apoptosis induced in CD4+ cells expressing gp160 of human immunodeficiency virus type 1. J Virol. 1994 Jan;68(1):390–399. doi: 10.1128/jvi.68.1.390-399.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  19. Meyaard L., Otto S. A., Keet I. P., Roos M. T., Miedema F. Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease. J Clin Invest. 1994 Mar;93(3):982–988. doi: 10.1172/JCI117105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miyawaki T., Uehara T., Nibu R., Tsuji T., Yachie A., Yonehara S., Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992 Dec 1;149(11):3753–3758. [PubMed] [Google Scholar]
  21. Mower D. A., Jr, Peckham D. W., Illera V. A., Fishbaugh J. K., Stunz L. L., Ashman R. F. Decreased membrane phospholipid packing and decreased cell size precede DNA cleavage in mature mouse B cell apoptosis. J Immunol. 1994 May 15;152(10):4832–4842. [PubMed] [Google Scholar]
  22. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  23. Oyaizu N., McCloskey T. W., Coronesi M., Chirmule N., Kalyanaraman V. S., Pahwa S. Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals. Blood. 1993 Dec 1;82(11):3392–3400. [PubMed] [Google Scholar]
  24. Ramsdell F., Seaman M. S., Miller R. E., Picha K. S., Kennedy M. K., Lynch D. H. Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death. Int Immunol. 1994 Oct;6(10):1545–1553. doi: 10.1093/intimm/6.10.1545. [DOI] [PubMed] [Google Scholar]
  25. Schnittman S. M., Greenhouse J. J., Psallidopoulos M. C., Baseler M., Salzman N. P., Fauci A. S., Lane H. C. Increasing viral burden in CD4+ T cells from patients with human immunodeficiency virus (HIV) infection reflects rapidly progressive immunosuppression and clinical disease. Ann Intern Med. 1990 Sep 15;113(6):438–443. doi: 10.7326/0003-4819-113-6-438. [DOI] [PubMed] [Google Scholar]
  26. Schnittman S. M., Lane H. C., Greenhouse J., Justement J. S., Baseler M., Fauci A. S. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6058–6062. doi: 10.1073/pnas.87.16.6058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  28. Singer G. G., Abbas A. K. 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):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
  29. Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
  30. Smith C. A., Gruss H. J., Davis T., Anderson D., Farrah T., Baker E., Sutherland G. R., Brannan C. I., Copeland N. G., Jenkins N. A. CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell. 1993 Jul 2;73(7):1349–1360. doi: 10.1016/0092-8674(93)90361-s. [DOI] [PubMed] [Google Scholar]
  31. Suda T., Takahashi T., Golstein P., Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993 Dec 17;75(6):1169–1178. doi: 10.1016/0092-8674(93)90326-l. [DOI] [PubMed] [Google Scholar]
  32. Tartaglia L. A., Weber R. F., Figari I. S., Reynolds C., Palladino M. A., Jr, Goeddel D. V. The two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9292–9296. doi: 10.1073/pnas.88.20.9292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tedder T. F., Matsuyama T., Rothstein D., Schlossman S. F., Morimoto C. Human antigen-specific memory T cells express the homing receptor (LAM-1) necessary for lymphocyte recirculation. Eur J Immunol. 1990 Jun;20(6):1351–1355. doi: 10.1002/eji.1830200622. [DOI] [PubMed] [Google Scholar]
  34. Trauth B. C., Klas C., Peters A. M., Matzku S., Möller P., Falk W., Debatin K. M., Krammer P. H. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989 Jul 21;245(4915):301–305. doi: 10.1126/science.2787530. [DOI] [PubMed] [Google Scholar]
  35. Tsuji T., Nibu R., Iwai K., Kanegane H., Yachie A., Seki H., Miyawaki T., Taniguchi N. Efficient induction of immunoglobulin production in neonatal naive B cells by memory CD4+ T cell subset expressing homing receptor L-selectin. J Immunol. 1994 May 1;152(9):4417–4424. [PubMed] [Google Scholar]
  36. Uehara T., Miyawaki T., Ohta K., Tamaru Y., Yokoi T., Nakamura S., Taniguchi N. Apoptotic cell death of primed CD45RO+ T lymphocytes in Epstein-Barr virus-induced infectious mononucleosis. Blood. 1992 Jul 15;80(2):452–458. [PubMed] [Google Scholar]
  37. Wang Z. Q., Dudhane A., Orlikowsky T., Clarke K., Li X., Darzynkiewicz Z., Hoffmann M. K. CD4 engagement induces Fas antigen-dependent apoptosis of T cells in vivo. Eur J Immunol. 1994 Jul;24(7):1549–1552. doi: 10.1002/eji.1830240714. [DOI] [PubMed] [Google Scholar]
  38. Wang Z. Q., Orlikowsky T., Dudhane A., Mittler R., Blum M., Lacy E., Riethmüller G., Hoffmann M. K. Deletion of T lymphocytes in human CD4 transgenic mice induced by HIV-gp120 and gp120-specific antibodies from AIDS patients. Eur J Immunol. 1994 Jul;24(7):1553–1557. doi: 10.1002/eji.1830240715. [DOI] [PubMed] [Google Scholar]
  39. Watanabe-Fukunaga R., Brannan C. I., Itoh N., Yonehara S., Copeland N. G., Jenkins N. A., Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol. 1992 Feb 15;148(4):1274–1279. [PubMed] [Google Scholar]
  40. Wognum A. W., Krystal G., Eaves C. J., Eaves A. C., Lansdorp P. M. Increased erythropoietin-receptor expression on CD34-positive bone marrow cells from patients with chronic myeloid leukemia. Blood. 1992 Feb 1;79(3):642–649. [PubMed] [Google Scholar]
  41. Yonehara S., Ishii A., Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. doi: 10.1084/jem.169.5.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. van Noesel C. J., Gruters R. A., Terpstra F. G., Schellekens P. T., van Lier R. A., Miedema F. Functional and phenotypic evidence for a selective loss of memory T cells in asymptomatic human immunodeficiency virus-infected men. J Clin Invest. 1990 Jul;86(1):293–299. doi: 10.1172/JCI114698. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES