Springer Seminars in Immunopathology

, Volume 19, Issue 3, pp 289–300 | Cite as

Receptors and ligands that mediate activation-induced death of T cells

  • Mark R. Alderson
  • David H. Lynch
Article

Conclusion

The critical roles played by Fas/FasL and TNF/TNFR in AICD, peripheral T cell deletion and clonal downsizing have become increasingly apparent over the last few years. Consequently, new approaches have become possible for manipulation of T cell-mediated immune responses in either a positive or negative manner. For example, in disease states where excessive AICD involving FasL and TNF is observed there lies the possibility of intervention using specific inhibitors of these apoptotic pathways such as soluble forms of Fas and TNFR or neutralizing antibodies to TNF/TNFR or Fas/FasL interactions. Alternatively, the recent demonstration that the apoptotic pathways induced by FasL and TNF involve ICE-like caspases has revealed an opportunity to regulate apoptosis using inhibitors of this pathway. Indeed, in vivo treatment with a tripeptide inhibitor of ICE-like proteases (Z-VAD.fmk) protects mice from Fas-mediated hepatitis and death [53]. Thus, a multi-faceted approach to the treatment of depletion of T cells arising from HIV infection may in the future include not only inhibitors of viral replication but also inhibitors of host cell apoptosis. In addition, treatment of tumors that express FasL may be aided by use of an inhibitor of Fas to allow generation of an anti-tumor T cell response or, alternatively, T cells reactive with the tumor may be expanded in vitro in the presence of Fas and TNF antagonists for use in adoptive immunotherapy. In the area of transplantation biology, transfection of the tissue to be transplanted with the gene for FasL may in some cases help prevent rejection of the graft by host T cells, although recent studies have indicated that so-called “immune privilege” does not result from simple expression of FasL. Moreover, the ability to induce selective elimination of antigen-reactive T cells by immunization in immune privileged sites (ACAID) may allow for induction of tolerance to antigens implicated in autoimmune disease. Finally, the recent demonstration that monocytes may be stimulated via CD4 cross-linking or treatment with M-CSF to induce AICD in T cells raises the possibility of loading these cells with antigen to induce tolerance by adoptive immunotherapy. Again, a strategy such as this might be used for the treatment of autoimmune disease or in the prevention of allograft rejection. On a cautionary note, however, it has become clear from recent studies that we are not in a position at present to manipulate T cell-mediated immune responses at will. Several studies in which the gene for FasL was transfected into cells to induce a state of “immune privilege” produced the opposite of the predicted effect. Further understanding of the apoptotic pathways that control the expansion and survival of T cells will undoubtedly allow the development of novel strategies for treatment of infectious disease, cancer, immunodeficiency and autoimmune disease.

Keywords

Apoptotic Pathway Allograft Rejection Adoptive Immunotherapy Cautionary Note Recent Demonstration 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abreu-Martin MT, Vidrich A, Lynch DH, Targan SR (1995) Divergent induction of apoptosis and IL-8 secretion in HT 29 cells in response to TNF-alpha and ligation of Fas antigen. J Immunol 155: 4147Google Scholar
  2. 2.
    Alderson MR, Armitage RJ, Maraskovsky E, Tough TW, Roux E, Schooley K, Ramsdell F, Lynch DH (1993) Fas transduces activation signals in normal human T lymphocytes. J Exp Med 178: 2231Google Scholar
  3. 3.
    Alderson MR, Smith CA, Tough TW, Davis-Smith T, Armitage RJ, Falk B, Roux E, Baker E, Sutherland GR, Din WS, Goodwin RG (1994) Molecular and biological characterization of human 4-1BB and its ligand. Eur J Immunol 24: 2219Google Scholar
  4. 4.
    Alderson MR, Tough TW, Braddy S, Davis-Smith T, Roux E, Schooley K, Miller RE, Lynch DH (1994) Regulation of apoptosis and T cell activation by Fas-specific mAb. Int Immunol 6: 1799Google Scholar
  5. 5.
    Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F, Lynch DH (1995) Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181: 71Google Scholar
  6. 6.
    Allison J, Georgiou HM, Strasser A, Vaux DL (1997) Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc Nail Acad Sci USA 94: 3943Google Scholar
  7. 7.
    Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thomberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature [letter]. Cell 87: 171Google Scholar
  8. 8.
    Ameisen JC, Capron A (1991) Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today 12: 102Google Scholar
  9. 9.
    Ayroldi E, Migliorati G, Cannarile L, Moraca R, Delfino DV, Riccardi C (1997) CD2 rescues T cells from T-cell receptor/CD3 apoptosis: a role for the Fas/Fas-L system. Blood 89: 3717Google Scholar
  10. 10.
    Badley AD, McElhinny JA, Leibson PJ, Lynch DH, Alderson MR, Paya CV (1996) Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J Virol 70: 199Google Scholar
  11. 11.
    Badley AD, Dockrell D, Simpson M, Schut R, Lynch DH, Leibson P, Paya CV (1997) Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor. J Exp Med 185: 55Google Scholar
  12. 12.
    Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly R-P, Finkel TH (1992) Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med 176: 1099Google Scholar
  13. 13.
    Baumler CB, Bohler T, Herr I, Benner A, Krammer PH, Debatin KM (1996) Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-l-infected children. Blood 88: 1741Google Scholar
  14. 14.
    Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC (1995) A role for CD95 ligand in preventing graft rejection. Nature 377: 630Google Scholar
  15. 15.
    Beutler B, Cerami A (1989) The biology of cachectin/TNF — a primary mediator of the host response. Annu Rev Immunol 7: 625Google Scholar
  16. 16.
    Brunner T, Mogil RJ, La Face D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF, et al (1995) Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373: 441Google Scholar
  17. 17.
    Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA Jr, Matis LA (1997) The role of Fas in autoimmune diabetes. Cell 89: 17Google Scholar
  18. 18.
    Cohen PL, Eisenberg RA (1991)Lpr andgld: Single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol 9: 243Google Scholar
  19. 19.
    Damle NK, Leytze G, Klussman K, Ledbetter JA (1993) Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CDl la/CD18-dependent mechanism. Eur J Immunol 23: 1513Google Scholar
  20. 20.
    Dhein J, Walczak H, Baumler C, Debatin KM, Krammer PH (1995) Autocrine T-cell suicide mediated by APO- 1/(Fas/CD95). Nature 373: 438Google Scholar
  21. 21.
    Estaquier J, Tanaka M, Suda T, Nagata S, Golstein P, Ameisen JC (1996) Fas-mediated apoptosis of CD4+ CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists. Blood 87: 4959Google Scholar
  22. 22.
    Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81: 935Google Scholar
  23. 23.
    Freiberg RA, Spencer DM, Choate KA, Duh HJ, Schreiber SL, Crabtree GR, Khavari PA (1997) Fas signal transduction triggers either proliferation or apoptosis in human fibroblasts. J Invest Dermatol 108: 215Google Scholar
  24. 24.
    Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, Krammer PH, Runkel L (1995) Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med 182: 1223Google Scholar
  25. 25.
    Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier, et al (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83: 793Google Scholar
  26. 26.
    Griffith TS, Ferguson TA (1997) The role of FasL-induced apoptosis in immune privilege. Immunol Today 18: 240Google Scholar
  27. 27.
    Griffith TS, Yu X, Hemdon JM, Green DR, Ferguson TA (1996) CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity 5: 7Google Scholar
  28. 28.
    Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bomand T, Fontana A, Lienard D, Cerottini J, Tschopp J (1996) Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274: 1363Google Scholar
  29. 29.
    Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66: 233Google Scholar
  30. 30.
    Ju ST, Panka DJ, Cui H, EttingerR. el-Khatib M, Sherr DH, Stanger BZ, Marshak-Rothstein A (1995) Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373: 444Google Scholar
  31. 31.
    Kang S-M, Schneider DB, Lin Z, Hanahan D, Dichek DA, Stock PG, Baekkeskov S (1997) Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 3: 738Google Scholar
  32. 32.
    Katsikis PD, Wunderlich ES, Smith CA, Herzenberg LA, Herzenberg LA (1995) Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 181: 2029Google Scholar
  33. 33.
    Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H (1995) Metalloproteinase-mediated release of human Fas ligand. J Exp Med 182: 1777Google Scholar
  34. 34.
    Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S (1997) Essential roles of the Fas ligand in the development of hepatitis. Nat Med 3: 409Google Scholar
  35. 35.
    Lau HT, Yu M, Fontana A, Stoeckert CJ Jr (1996) Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273: 109Google Scholar
  36. 36.
    Laurence J, Mitra D, Steiner M, Lynch DH, Siegal FP, Staiano-Coico L (1996) Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J Clin Invest 97: 672Google Scholar
  37. 37.
    Lynch DH, Watson ML, Alderson MR, Baum PR, Miller RE, Tough T, Gibson M, Davis-Smith T, Smith CA, Hunter K, Bhat D, Din W, Goodwin RG, Seldin MF (1994) The mouse Fas-ligand gene is mutated ingld mice and is part of a TNF family gene cluster. Immunity 1: 131Google Scholar
  38. 38.
    Lynch DH, Ramsdell F, Alderson MR (1995) Fas and FasL in the homeostatic regulation of immune responses. Immunol Today 16: 569Google Scholar
  39. 39.
    Mapara MY, Bargou R, Zugck C, Döhner H, Ustaoglu F, Jonker RR, Krammer PH, Dörken B (1993) APO-1 mediated apoptosis or proliferation in human chronic B lymphocytic leukemia: correlation with bel-2 oncogene expression. Eur J Immunol 23: 702Google Scholar
  40. 40.
    Mariani SM, Matiba B, Baumler C, Krammer PH (1995) Regulation of cell surface APO-1/Fas (CD95) ligand expression by metalloproteases. Eur J Immunol 25: 2303Google Scholar
  41. 41.
    Mitra D, Steiner M, Lynch DH, Staiano-Coico L, Laurence J (1996) HIV-1 upregulates Fas ligand expression in CD4+ T cells in vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid. Immunology 87: 581Google Scholar
  42. 42.
    Mollereau B, Deckert M, Deas O, Rieux-Laucat F, Hirsch F, Bernard A, Fischer A, Lynch DH, Charpentier B, Le Deist F, Senik A (1996) CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation. J Immunol 156: 3184Google Scholar
  43. 43.
    Munn DH, Pressey J, Beall AC, Hodes R, Alderson MR (1996) Selective activation-induced apoptosis of peripheral T cells imposed by macrophages. A potential mechanism of antigen-specific peripheral lymphocyte deletion. J Immunol 156: 523Google Scholar
  44. 44.
    Nagata S (1997) Apoptosis by death factor. Cell 88: 355Google Scholar
  45. 45.
    Newell MK, Haughn LJ, Maroun CR, Julius MH (1990) Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature 347: 286Google Scholar
  46. 46.
    O'Connell J, O'Sullivan GC, Collins JK, Shanahan F (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184: 1075Google Scholar
  47. 47.
    Oehm A, Behrmann I, Falk W, et al (1992) Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem 267: 10709Google Scholar
  48. 48.
    Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itch N, Suda T, Nagata S (1993) Lethal effect of the anti-Fas antibody in mice. Nature 364: 806Google Scholar
  49. 49.
    Oyaizu N, McCloskey TW, Coronesi M, Chirmule N, Kalyanaraman VS, Pahwa S (1993) 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 82: 3392Google Scholar
  50. 50.
    Oyaizu N, Adachi Y, Hashimoto F, McCloskey TW, Hosaka N, Kayagaki N, Yagita H, Pahwa S (1997) Monocytes express Fas ligand upon CD4 cross-linking and induce CD4+ T cells apoptosis: a possible mechanism of bystander cell death in HIV infection. J Immunol 158: 2456Google Scholar
  51. 51.
    Ramsdell F, Seaman MS, Miller RE, Picha KS, Kennedy MK, Lynch DH (1994) Differential ability of Thl and Th2 T cells to express Fas ligand and to undergo activation-induced cell death. Int Immunol 6: 1545Google Scholar
  52. 52.
    Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, Villartay JP de (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268: 1347Google Scholar
  53. 53.
    Rodriguez I, Matsuura K, Ody C, Nagata S, Vassalli P (1996) Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death. J Exp Med 184: 2067Google Scholar
  54. 54.
    Russell JH, Wang R (1993) Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells. Eur J Immunol 23: 2379Google Scholar
  55. 55.
    Russell JH, Rush B, Weaver C, Wang R (1993) Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide. Proc Natl Acad Sci USA 90: 4409Google Scholar
  56. 56.
    Schwarz H, Blanco FJ, Kempis J von, Valbracht J, Lotz M (1996) ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T -lymphocyte proliferation and survival. Blood 87: 2839Google Scholar
  57. 57.
    Seino K, Kayagaki N, Okumura K, Yagita H (1997) Antitumor effect of locally produced CD95 ligand. Nat Med 3: 165Google Scholar
  58. 58.
    Singer GG, Abbas AK (1994) The Fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity 1: 365Google Scholar
  59. 59.
    Sloand EM, Young NS, Kumar P, Weichold FF, Sato T, Maciejewski JP (1997) Role of Fas ligand and receptor in the mechanism of T-cell depletion in acquired immunodeficiency syndrome: effect on CD4+ lymphocyte depletion and human immunodeficiency virus replication. Blood 89: 1357Google Scholar
  60. 60.
    Smith CA, Farrah T, Goodwin RG (1994) The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76: 959Google Scholar
  61. 61.
    Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, Mariani SM, Stremmel W, Krammer PH, Galle PR (1996) Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells — a mechanism of immune evasion? Nat Med 2: 1361Google Scholar
  62. 62.
    Suda T, Takahashi T, Golstein P, Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75: 1169Google Scholar
  63. 63.
    Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S (1994) Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76: 969Google Scholar
  64. 64.
    Tartaglia LA, Goeddel DV, Reynolds C, Figari IS, Weber RF, Fendly BM, Palladino MA Jr (1993) Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. J Immunol 151: 4637Google Scholar
  65. 65.
    Trauth BC, Klas C, Peters AML, Matzku S, Möller P, Falk W, Debatin K-M, Krammer PH (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245: 301Google Scholar
  66. 66.
    Varadhachary AS, Perdow SN, Hu C, Ramanarayanan M, Salgame P (1997) Differential ability of T cell subsets to undergo activation-induced cell death. Proc Natl Acad Sci USA 94: 5778Google Scholar
  67. 67.
    Walker PR, Saas P, Dietrich PY (1997) Role of Fas ligand (CD95L) in immune escape: the tumor cell strikes back.J Immunol 158: 4521Google Scholar
  68. 68.
    Wang Z, Dudhane A, Orlikowsky T, Clarke K, Li X, Darzynkiewicz Z, Hoffmann MK (1994) CD4 engagement induces Fas antigen-dependent apoptosis of T cells in vivo. Eur J Immunol 24: 1549Google Scholar
  69. 69.
    Wang Z, Orlikowsky T, Dudhane A, Mittler R, Blum M, Lacy E, Riethmüller G, Hoffmann MK (1994) Deletion of T lymphocytes in human CD4 transgenic mice induced by HIV-gp120 and gp120-specific antibodies from AIDS patients. Ent J Immunol 24: 1553Google Scholar
  70. 70.
    Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314Google Scholar
  71. 71.
    Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH (1995) Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375: 497Google Scholar
  72. 72.
    Yonehara S, Ishii A, Yonehara M (1989) A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med 169: 1747Google Scholar
  73. 73.
    Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L, Sato T, Reed JC, Green D, Swain SL (1997) Unequal death in T helper cell (Th)1 and Th2 effectors: Thl, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 185: 1837Google Scholar
  74. 74.
    Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ (1995) Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377: 348Google Scholar

Copyright information

© Springer-Verlag 1998

Authors and Affiliations

  • Mark R. Alderson
    • 1
  • David H. Lynch
    • 2
  1. 1.Department of Immunology, Corixa Corporation SeattleUSA
  2. 2.Department of Immunobiology, Immunex CorporationSeattleUSA

Personalised recommendations