Fas Signaling pp 118-127 | Cite as

Fas-Activation, Development and Homeostasis of T Cells

  • Georg Häcker
Part of the Medical Intelligence Unit book series (MIUN)


Fas (APO-1/CD95) is found on various cells of the immune system where its expression depends on differentiation and activation status of the cells. Analysis of the function of Fas on T lymphocytes has been the objective of many studies. Like in most cells carrying Fas, ligation by antibodies or FasL can induce apoptosis in T cells. Over the years, Fas has been implicated in the regulation of many aspects of T cell physiology. However, more recent data have challenged some of the earlier views, and the matter of the importance of Fas for life and death of a T cell is, in some aspects, controversial. Fas has been suggested to play a role in selection/development of a T cell, the activation of a resting T cell and the homeostasis of a T cell population, an area that has attracted much attention. In this chapter I will focus on the discussion of the data available on the role of Fas in these fields. The role of FasL on activated T cells will be covered briefly.


Immune Privilege Activation Induce Cell Death Thymic Selection Autoimmune Uveitis Autoimmune Lymphoproliferative Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ogasawara J, Watanabe-Fukunaga R, Adachi M et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993; 364:806–809.PubMedCrossRefGoogle Scholar
  2. 2.
    Drappa J, Brot N, Elkon KB. The Fas protein is expressed at high levels on CD4+CD8+ thy-mocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr. Proc Natl Acad Sci USA 1993; 90:10340–10344.PubMedCrossRefGoogle Scholar
  3. 3.
    Miyawaki T, Uehara T, Nibu R et al. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol 1992; 149:3753–3758.PubMedGoogle Scholar
  4. 4.
    Krammer PH, Dhein J, Walczak H et al. The role of APO-1-mediated apoptosis in the immune system. Immunol Rev 1994; 142:175–191.PubMedCrossRefGoogle Scholar
  5. 5.
    Klas C, Debatin KM, Jonker RR et al. Activation interferes with the APO-1 pathway in mature human T cells. Int Immunol 1993; 5:625–630.PubMedCrossRefGoogle Scholar
  6. 6.
    Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 1991; 353:858–861.PubMedCrossRefGoogle Scholar
  7. 7.
    Watanabe-Fukunaga R, Brannan CI, Copeland NG et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992; 356:314–317.PubMedCrossRefGoogle Scholar
  8. 8.
    Takahashi T, Tanaka M, Brannan CI et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 1994; 76:969–976.PubMedCrossRefGoogle Scholar
  9. 9.
    Renno T, Hahne M, Tschopp J et al. Peripheral T cells undergoing superantigen-induced apoptosis in vivo express B220 and upregulate Fas and Fas ligand. J Exp Med 1996; 183:431–437.PubMedCrossRefGoogle Scholar
  10. 10.
    Adachi M, Suematsu S, Kondo T et al. Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nat Genet 1995; 11:294–300.PubMedCrossRefGoogle Scholar
  11. 11.
    Rieux-Laucat F, Le Deist F, Fischer A. Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death Differ 2003; 10:124–133.PubMedCrossRefGoogle Scholar
  12. 12.
    Werlen G, Hausmann B, Naeher D et al. Signaling life and death in the thymus: timing is every-thing. Science 2003; 299:1859–1863.PubMedCrossRefGoogle Scholar
  13. 13.
    Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 1994; 372:100–103.PubMedCrossRefGoogle Scholar
  14. 14.
    Herron LR, Eisenberg RA, Roper E et al. Selection of the T cell receptor repertoire in Lpr mice. J Immunol 1993; 151:3450–3459.PubMedGoogle Scholar
  15. 15.
    Singer GG, Abbas AK. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity 1994; 1:365–371.PubMedCrossRefGoogle Scholar
  16. 16.
    Geppert TD, Wacholtz MC, Davis LS et al. Activation of human T4 cells by cross-linking class I MHC molecules. J Immunol 1988; 140:2155–2164.PubMedGoogle Scholar
  17. 17.
    Alderson MR, Armitage RJ, Maraskovsky E et al. Fas transduces activation signals in normal human T lymphocytes. J Exp Med 1993; 178:2231–2235.PubMedCrossRefGoogle Scholar
  18. 18.
    Kennedy NJ, Kataoka T, Tschopp J et al. Caspase Activation Is Required for T Cell Proliferation. J Exp Med 1999; 190:1891–1896.PubMedCrossRefGoogle Scholar
  19. 19.
    Newton K, Harris AW, Bath ML et al. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J 1998; 17:706–718.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang J, Cado D, Chen A et al. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 1998; 392:296–300.PubMedCrossRefGoogle Scholar
  21. 21.
    Walsh CM, Wen BG, Chinnaiyan AM et al. A role for FADD in T cell activation and development. Immunity 1998; 8:439–449.PubMedCrossRefGoogle Scholar
  22. 22.
    Zornig M, Hueber AO, Evan G. P53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice. Curr Biol 1998; 8:467–470.PubMedCrossRefGoogle Scholar
  23. 23.
    Lens SM, Kataoka T, Former KA et al. The caspase 8 inhibitor c-FLIP(L) modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes. Mol Cell Biol 2002; 22:5419–5433.PubMedCrossRefGoogle Scholar
  24. 24.
    Salmena L, Lemmers B, Hakem A et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 2003; 17:883–895.PubMedCrossRefGoogle Scholar
  25. 25.
    Newton K, Strasser A. Caspases signal not only apoptosis but also antigen-induced activation in cells of the immune system. Genes Dev 2003; 17:819–825.PubMedCrossRefGoogle Scholar
  26. 26.
    Altman A, Theofilopoulos AN, Weiner R et al. Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2. J Exp Med 1981; 154:791–808.PubMedCrossRefGoogle Scholar
  27. 27.
    Landolfi MM, Van Houten N, Russell JQ et al. CD2-CD4-CD8-lymph node T lymphocytes in MRL lpr/lpr mice are derived from a CD2+CD4+CD8+ thymic precursor. J Immunol 1993; 151:1086–1096.PubMedGoogle Scholar
  28. 28.
    Green DR, Droin N, Pinkoski M. Activation-induced cell death in T cells. Immunol Rev 2003; 193:70–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Hildeman DA, Zhu Y, Mitchell TC et al. Molecular mechanisms of activated T cell death in vivo. Curr Opin Immunol 2002; 14:354–359.PubMedCrossRefGoogle Scholar
  30. 30.
    Mercep M, Weissman AM, Frank SJ et al. Activation-driven programmed cell death and T cell receptor zeta eta expression. Science 1989; 246:1162–1165.PubMedCrossRefGoogle Scholar
  31. 31.
    Shi YF, Sahai BM, Green DR. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 1989; 339:625–626.PubMedCrossRefGoogle Scholar
  32. 32.
    Dhein J, Walczak H, Baumler C et al. Autocrine T-cell suicide mediated by APO-l/(Fas/CD95). Nature 1995; 373:438–441.PubMedCrossRefGoogle Scholar
  33. 33.
    Brunner T, Mogil RJ, LaFace D et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 1995; 373:441–444.PubMedCrossRefGoogle Scholar
  34. 34.
    Ju ST, Panka DJ, Cui H et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 1995; 373:444–448.PubMedCrossRefGoogle Scholar
  35. 35.
    Alderson MR, Tough TW, Davis-Smith T et al. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 1995; 181:71–77.PubMedCrossRefGoogle Scholar
  36. 36.
    Yang Y, Mercep M, Ware CF et al. 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; 181:1673–1682.PubMedCrossRefGoogle Scholar
  37. 37.
    Kawabe Y, Ochi A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature 1991; 349:245–248.PubMedCrossRefGoogle Scholar
  38. 38.
    Vella AT, McCormack JE, Linsley PS et al. Lipopolysaccharide interferes with the induction of peripheral T cell death. Immunity 1995; 2:261–270.PubMedCrossRefGoogle Scholar
  39. 39.
    Mogil RJ, Radvanyi L, Gonzalez-Quintial R et al. Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. Int Immunol 1995; 7:1451–1458.PubMedCrossRefGoogle Scholar
  40. 40.
    Renno T, Hahne M, Tschopp J et al. Peripheral T cells undergoing superantigen-induced apoptosis in vivo express B220 and upregulate Fas and Fas ligand. J Exp Med 1996; 183:431–437.PubMedCrossRefGoogle Scholar
  41. 41.
    Miethke T, Vabulas R, Bittlingmaier R et al. Mechanisms of peripheral T cell deletion: anergized T cells are Fas resistant but undergo proliferation-associated apoptosis. Eur J Immunol 1996; 26:1459–1467.PubMedCrossRefGoogle Scholar
  42. 42.
    Zheng L, Fisher G, Miller RE et al. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 1995; 377:348–351.PubMedCrossRefGoogle Scholar
  43. 43.
    Hildeman DA, Zhu Y, Mitchell TC et al. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 2002; 16:759–767.PubMedCrossRefGoogle Scholar
  44. 44.
    Kim C, Siminovitch KA, Ochi A. Reduction of lupus nephritis in MRL/lpr mice by a bacterial superantigen treatment. J Exp Med 1991; 174:1431–1437.PubMedCrossRefGoogle Scholar
  45. 45.
    Zimmermann C, Rawiel M, Blaser C et al. Homeostatic regulation of CD8+ T cells after antigen challenge in the absence of Fas (CD95). Eur J Immunol 1996; 26:2903–2910.PubMedCrossRefGoogle Scholar
  46. 46.
    Bouillet P, Metcalf D, Huang DC et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286:1735–1738.PubMedCrossRefGoogle Scholar
  47. 47.
    Strasser A, Harris AH, Huang DCS et al. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J 1996; 14:6136–6147.Google Scholar
  48. 48.
    Smith KGC, Strasser A, Vaux DL. CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (fas/APO-l)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J 1996; 15:5167–5176.PubMedGoogle Scholar
  49. 49.
    Rescigno M, Piguet V, Valzasina B et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-l beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: A new role for Fas ligand in inflammatory responses. J Exp Med 2000; 192:1661–1668.PubMedCrossRefGoogle Scholar
  50. 50.
    Restifo NP. Not so Fas: Reevaluating the mechanisms of immune privilege and tumor escape. Nat Med 2000; 6:493–495.PubMedCrossRefGoogle Scholar
  51. 51.
    Bellgrau D, Gold D, Selawry H et al. A role for CD95 ligand in preventing graft rejection. Nature 1995; 377:630–632.PubMedCrossRefGoogle Scholar
  52. 52.
    Griffith TS, Brunner T, Fletcher SM et al. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 1995; 270:1189–1192.PubMedCrossRefGoogle Scholar
  53. 53.
    Allison J, Georgiou HM, Strasser A et al. Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc Natl Acad Sci USA 1997; 94:3943–3947.PubMedCrossRefGoogle Scholar
  54. 54.
    Vaux DL. Immunology. Ways around rejection. Nature 1998; 394:133.PubMedCrossRefGoogle Scholar
  55. 55.
    Green DR, Ferguson TA. The role of Fas ligand in immune privilege. Nat Rev Mol Cell Biol 2001; 2:917–924.PubMedCrossRefGoogle Scholar
  56. 56.
    Wahlsten JL, Gitchell HL, Chan CC et al. Fas and Fas ligand expressed on cells of the immune system, not on the target tissue, control induction of experimental autoimmune uveitis. J Immunol 2000; 165:5480–5486.PubMedGoogle Scholar
  57. 57.
    Restifo NP. Countering the ‘counterattack’ hypothesis. Nat Med 2001; 7:259-.PubMedCrossRefGoogle Scholar
  58. 58.
    Niederkorn JY. The immune privilege of corneal grafts. J Leukoc Biol 2003; 74:167–171.PubMedCrossRefGoogle Scholar
  59. 59.
    Takeda K, Hayakawa Y, Smyth MJ et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001; 7:94–100.PubMedCrossRefGoogle Scholar
  60. 60.
    Lowin B, Hahne M, Mattmann C et al. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994; 370:650–652.PubMedCrossRefGoogle Scholar
  61. 61.
    Schmaltz C, Alpdogan O, Horndasch KJ et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 2001; 97:2886–2895.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  • Georg Häcker
    • 1
  1. 1.Institute for Medical MicrobiologyTechnische Universität MünchenMünichGermany

Personalised recommendations