T cell life and death signalling via TNF-receptor family members

Current Opinion in Immunology

Volumn 12, Issue 3, 2000, Pages 316-322

  Screaton, Gavin ^a,b   Xu, Xiao Ning ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b JOHN RADCLIFFE HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

FAS LIGAND; TUMOR NECROSIS FACTOR RECEPTOR;

APOPTOSIS; CELL DEATH; EFFECTOR CELL; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE;

EID: 0034050278     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(00)00093-5     Document Type: Review

References (100)

1. Lenardo M., Chan K.M., Hornung F., McFarland H., Siegel R., Wang J., Zheng L. Mature T lymphocyte apoptosis - immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol. 17:1999;221-253.
2. Rathmell J.C., Thompson C.B. The central effectors of cell death in the immune system. Annu Rev Immunol. 17:1999;781-828.
3. Gravestein L.A., Borst J. Tumor necrosis factor receptor family members in the immune system. Semin Immunol. 10:1998;423-434.
4. Kwon B., Youn B., Kwon B. Functions of newly identified members of the tumor necrosis factor receptor/ligand superfamilies in lymphocytes. Curr Opin Immunol. 11:1999;340-345.
5. Nagata S. Apoptosis by death factor. Cell. 88:1997;355-365.
6. Golstein P. Cell death: TRAIL and its receptors. Curr Biol. 7:1997;R750-R753.
7. Pan G., Bauer J.H., Haridas V., Wang S., Liu D., Yu G., Vincenz C., Aggarwal B.B., Ni J., Dixit V.M. Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett. 431:1998;351-356.
8. Green D.R., Ware C.F. Fas-ligand: privilege and peril. Proc Natl Acad Sci USA. 94:1997;5986-5990.
9. Bonfoco E., Stuart P.M., Brunner T., Lin T., Griffith T.S., Gao Y., Nakajima H., Henkart P.A., Ferguson T.A., Green D.R. Inducible nonlymphoid expression of Fas ligand is responsible for superantigen-induced peripheral deletion of T cells. Immunity. 9:1998;711-720.
10. Walker P.R., Saas P., Dietrich P.Y. Tumor expression of Fas ligand (CD95L) and the consequences. Curr Opin Immunol. 10:1998;564-572.
11. Zauli G., Gibellini D., Secchiero P., Dutartre H., Olive D., Capitani S., Collette Y. Human immunodeficiency virus type 1 Nef protein sensitizes CD4(+) T lymphoid cells to apoptosis via functional upregulation of the CD95/CD95 ligand pathway. Blood. 93:1999;1000-1010.
12. Xu X., Laffert B., Screaton G., Kraft M., Wolf D., Kolanus W., Mongkolsapaya J., McMichael A., Baur A. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 189:1999;1489-1496.
13. Zhao S., Asgary Z., Wang Y., Goodwin R., Andreeff M., Younes A. Functional expression of TRAIL by lymphoid and myeloid tumour cells. Br J Haematol. 106:1999;827-832.
14. Giovarelli M., Musiani P., Garotta G., Ebner R., Di Carlo E., Kim Y., Cappello P., Rigamonti L., Bernabei P., Novelli F.et al. A 'stealth effect': adenocarcinoma cells engineered to express TRAIL elude tumor-specific and allogeneic T cell reactions. J Immunol. 163:1999;4886-4893. TRAIL transfected cells are resistant to CTL lysis and do not prime a memory CTL response in vivo.
15. •].
16. •], reports that the TRAIL-DR5 complex shows differences in interacting residues from the TNF-TNFR1 complex; the paper gives some insights into receptor-ligand specificity.
17. Banner D.W., D'Arcy A., Janes W., Gentz R., Schoenfeld H.J., Broger C., Loetscher H., Lesslauer W. Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Cell. 73:1993;431-445.
18. Yang X., Khosravi-Far R., Chang H.Y., Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 89:1997;1067-1076.
19. Chang H.Y., Nishitoh H., Yang X., Ichijo H., Baltimore D. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science. 281:1998;1860-1863.
20. Chang H.Y., Yang X., Baltimore D. Dissecting Fas signalling with an altered-specificity death-domain mutant: requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation. Proc Natl Acad Sci USA. 96:1999;1252-1256.
21. Michaelson J.S., Bader D., Kuo F., Kozak C., Leder P. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13:1999;1918-1923.
22. Torii S., Egan D.A., Evans R.A., Reed J.C. Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J. 18:1999;6037-6049.
23. Hollenbach A.D., Sublett J.E., McPherson C.J., Grosveld G. The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx. EMBO J. 18:1999;3702-3711.
24. Imai Y., Kimura T., Murakami A., Yajima N., Sakamaki K., Yonehara S. The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis. Nature. 398:1999;777-785.
25. Koonin E.V., Aravind L., Hofmann K., Tschopp J., Dixit V.M. Apoptosis. Searching for FLASH domains. Nature. 401:1999;662-663.
26. Ashkenazi A., Dixit V.M. Death receptors: signalling and modulation. Science. 281:1998;1305-1308.
27. Lin Y., Devin A., Rodriguez Y., Liu Z.G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13:1999;2514-2526.
28. Mori S., Murakami-Mori K., Nakamura S., Ashkenazi A., Bonavida B. Sensitization of AIDS-Kaposi's sarcoma cells to Apo-2 ligand-induced apoptosis by actinomycin D. J Immunol. 162:1999;5616-5623.
29. Alexander-Miller M.A., Derby M.A., Sarin A., Henkart P.A., Berzofsky J.A. Supraoptimal peptide-major histocompatibility complex causes a decrease in bcl-2 levels and allows tumor necrosis factor alpha receptor II-mediated apoptosis of cytotoxic T lymphocytes. J Exp Med. 188:1998;1391-1399.
30. Herbein G., Mahlknecht U., Batliwalla F., Gregersen P., Pappas T., Butler J., O'Brien W.A., Verdin E. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature. 395:1998;189-194.
31. Prasad K.V., Ao Z., Yoon Y., Wu M.X., Rizk M., Jacquot S., Schlossman S.F. CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proc Natl Acad Sci USA. 94:1997;6346-6351.
32. Chiarle R., Podda A., Prolla G., Podack E.R., Thorbecke G.J., Inghirami G. CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. J Immunol. 163:1999;194-205.
33. Hess S., Engelmann H. A novel function of CD40: induction of cell death in transformed cells. J Exp Med. 183:1996;159-167.
34. Browning J.L., Miatkowski K., Sizing I., Griffiths D., Zafari M., Benjamin C.D., Meier W., Mackay F. Signalling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J Exp Med. 183:1996;867-878.
35. Zhai Y., Guo R., Hsu T.L., Yu G.L., Ni J., Kwon B.S., Jiang G.W., Lu J., Tan J., Ugustus M.et al. LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J Clin Invest. 102:1998;1142-1151.
36. •].
37. •].
38. •] find an indirect killing pathway leading from stimulation of surface receptors and leading to death induced through the transcription of TNF/FasL and/or increased sensitivity to killing via the DD-containing receptors TNFR1 and Fas.
39. Pimentel-Muinos F.X., Seed B. Regulated commitment of TNF receptor signalling: a molecular switch for death or activation. Immunity. 11:1999;783-793. The authors examine apoptosis in Jurkat cells (these usually express only TNFR1), which is induced by transfection of TNFR2. Such transfected cells became sensitive to apoptosis despite the generation of a strong NF-κB transcriptional response. RIP-lacking Jurkat cells are insensitive to TNFR2 mediated death and are also insensitive to TNFR1 mediated death even in the presence of a dominant negative IκB to block the NF-κB response. Co-immunoprecipitation is used to establish a TNFR2-TRAF2-RIP-FADD bridge from TNFR2 to the apoptotic cascade. Further it is shown that RIP is induced by T cell activation and that retroviral transfection of an antisense RIP construct reduced sensitivity to TNF in T cell blasts.
40. Kelliher M.A., Grimm S., Ishida Y., Kuo F., Stanger B.Z., Leder P. The death domain kinase RIP mediates the TNF-induced NF-kappa B signal. Immunity. 8:1998;297-303.
41. Newton K., Harris A.W., Bath M.L., Smith K.G.C., Strasser A. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17:1998;706-718.
42. Zornig M., Hueber A.O., Evan G. p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice. Curr Biol. 8:1998;467-470.
43. 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. 178:1993;2231-2235.
44. Rathmell J.C., Townsend S.E., Xu J.C., Flavell R.A., Goodnow C.C. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell. 87:1996;319-329.
45. + cells are costimulated by Fas ligation.
46. ••].
47. ••] use fluorogenic caspase substrates and caspase inhibitors to demonstrate caspase cleavage during lymphocyte activation and the requirement of this cleavage for subsequent cell proliferation.
48. Malinin N.L., Boldin M.P., Kovalenko A.V., Wallach D. MAP3K-related kinase involved in NF-kappa B induction by TNF, CD95 and IL-1. Nature. 385:1997;540-544.
49. Dudley E., Hornung F., Zheng L., Scherer D., Ballard D., Lenardo M. NF-kappa B regulates Fas/APO-1/CD95- and TCR-mediated apoptosis of T lymphocytes. Eur J Immunol. 29:1999;878-886.
50. Wallach D., Varfolomeev E.E., Malinin N.L., Goltsev Y.V., Kovalenko A.V., Boldin M.P. Tumor necrosis factor receptor and Fas signalling mechanisms. Annu Rev Immunol. 17:1999;331-367.
51. Scaffidi C., Kirchhoff S., Krammer P.H., Peter M.E. Apoptosis signalling in lymphocytes. Curr Opin Immunol. 11:1999;277-285.
52. Lacey D.L., Timms E., Tan H.L., Kelley M.J., Dunstan C.R., Burgess T., Elliott R., Colombero A., Elliott G., Scully S.et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 93:1998;165-176.
53. Anderson D.M., Maraskovsky E., Billingsley W.L., Dougall W.C., Tometsko M.E., Roux E.R., Teepe M.C., DuBose R.F., Cosman D., Galibert L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 390:1997;175-179.
54. Emery J.G., McDonnell P., Burke M.B., Deen K.C., Lyn S., Silverman C., Dul E., Appelbaum E.R., Eichman C., DiPrinzio R.et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 273:1998;14363-14367.
55. Pitti R.M., Marsters S.A., Lawrence D.A., Roy M., Kischkel F.C., Dowd P., Huang A., Donahue C.J., Sherwood S.W., Baldwin D.T.et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 396:1998;699-703. This report describes the cloning of a decoy for FasL. It is also suggested that this molecule plays a role in immune evasion by tumours.
56. Yu K.Y., Kwon B., Ni J., Zhai Y., Ebner R., Kwon B.S. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem. 274:1999;13733-13736.
57. Papoff G., Cascino I., Eramo A., Starace G., Lynch D.H., Ruberti G. An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. J Immunol. 156:1996;4622-4630.
58. Kitson J., Raven T., Jiang Y-P., Goeddel D.V., Giles K.M., Pun K-T., Grinham C.J., Brown R., Farrow S.N. A death-domain-containing receptor that mediates apoptosis. Nature. 384:1996;372-375.
59. Screaton G.R., Xu X.N., Olsen A.L., Cowper A.E., Tan R., McMichael A.J., Bell J.I. LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. Proc Natl Acad Sci USA. 94:1997;4615-4619.
60. Seckinger P., Vey E., Turcatti G., Wingfield P., Dayer J.M. Tumor necrosis factor inhibitor: purification, NH2-terminal amino acid sequence and evidence for anti-inflammatory and immunomodulatory activities. Eur J Immunol. 20:1990;1167-1174.
61. Smith C.A., Davis T., Anderson D., Solam L., Beckmann M.P., Jerzy R., Dower S.K., Cosman D., Goodwin R.G. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 248:1990;1019-1023.
62. Alcami A., Smith G.L. Cytokine receptors encoded by poxviruses: a lesson in cytokine biology. Immunol Today. 16:1995;474-478.
63. Lurain N.S., Kapell K.S., Huang D.D., Short J.A., Paintsil J., Winkfield E., Benedict C.A., Ware C.F., Bremer J.W. Human cytomegalovirus UL144 open reading frame: sequence hypervariability in low-passage clinical isolates. J Virol. 73:1999;10040-10050. The description of a CMV open reading frame deleted in normal laboratory strains. The receptor does not seem to get to the cell surface and does not bind any currently identified ligand molecules.
64. Tanaka M., Itai T., Adachi M., Nagata S. Downregulation of Fas ligand by shedding. Nat Med. 4:1998;31-36.
65. Suda T., Hashimoto H., Tanaka M., Ochi T., Nagata S. Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing. J Exp Med. 186:1997;2045-2050.
66. Schneider P., Holler N., Bodmer J.L., Hahne M., Frei K., Fontana A., Tschopp J. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med. 187:1998;1205-1213.
67. Mariani S.M., Krammer P.H. Differential regulation of TRAIL and CD95 ligand in transformed cells of the T and B lymphocyte lineage. Eur J Immunol. 28:1998;973-982.
68. Martinez-Lorenzo M.J., Anel A., Gamen S., Monle N.I., Lasierra P., Larrad L., Pineiro A., Alava M.A., Naval J. Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. J Immunol. 163:1999;1274-1281.
69. Thomas W.D., Hersey P. TNF related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol. 161:1998;2195-2200.
70. Zamai L., Ahmad M., Bennett I.M., Azzoni L., Alnemri E.S., Perussia B. Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med. 188:1998;2375-2380.
71. Fanger N.A., Maliszewski C.R., Schooley K., Griffith T.S. Human dendritic cells mediate cellular apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Exp Med. 190:1999;1155-1164.
72. Kayagaki N., Yamaguchi N., Nakayama M., Takeda K., Akiba H., Tsutsui H., Okamura H., Nakanishi K., Okumura K., Yagita H. Expression and function of TNF related apoptosis-inducing ligand on murine activated NK cells. J Immunol. 163:1999;1906-1913.
73. Kayagaki N., Yamaguchi N., Nakayama M., Eto H., Okumura K., Yagita H. Type I interferons (IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on human T cells: a novel mechanism for the antitumor effects of type I IFNs. J Exp Med. 189:1999;1451-1460.
74. Kayagaki N., Yamaguchi N., Nakayama M., Kawasaki A., Akiba H., Okumura K., Yagita H. Involvement of TNF related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol. 162:1999;2639-2647.
75. Pan G., Ni J., Wei Y.F., Yu G.L., Gentz R., Dixit V.M. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 277:1997;815-818.
76. Sheridan J.P., Marsters S.A., Pitti R.M., Guerney A., Skubach M., Baldwin D., Ramakrishnan L., Gray C.L., Baker K., Wood W.I.et al. Control of TRAIL-induced apoptosis by a family of signalling and decoy receptors. Science. 277:1997;818-821.
77. Degli Esposti M.A., Smolak P.J., Walczak H., Waugh J., Huang C.P., DuBose R.F., Goodwin R.G., Smith C.A. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med. 186:1997;1165-1170.
78. Mongkolsapaya J., Cowper A.E., Xu X.N., Morris G., McMichael A.J., Bell J.I., Screaton G.R. Lymphocyte inhibitor of TRAIL (TNF related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL. J Immunol. 160:1998;3-6.
79. Marsters S.A., Sheridan J.P., Pitti R.M., Huang A., Skubatch M., Baldwin D., Yuan J., Gurney A., Goddard A.D., Godowski P., Ashkenazi A. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol. 7:1997;1003-1006.
80. Degli Esposti M.A., Dougall W.C., Smolak P.J., Waugh J.Y., Smith C.A., Goodwin R.G. The novel receptor TRAIL-R4 induces NF-kappa B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity. 7:1997;813-820.
81. Pan G., Ni J., Yu G., Wei Y.F., Dixit V.M. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett. 424:1998;41-45.
82. ••].
83. ••] describing the use of TRAIL to treat tumours transplanted into mice. The latter report demonstrates both efficacy and lack of side effects in mice and primates.
84. Griffith T.S., Lynch D.H. TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol. 10:1998;559-563.
85. Griffith T.S., Chin W.A., Jackson G.C., Lynch D.H., Kubin M.Z. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol. 161:1998;2833-2840.
86. Griffith T.S., Rauch C.T., Smolak P.J., Waugh J.Y., Boiani N., Lynch D.H., Smith C.A., Goodwin R.G., Kubin M.Z. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol. 162:1999;2597-2605.
87. Zhang X.D., Franco A., Myers K., Gray C., Nguyen T., Hersey P. Relation of TNF related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res. 59:1999;2747-2753. A report looking at expression of the TRAIL receptors compared with sensitivity to TRAIL in a large panel of melanomas. Expression was quantified by fluorescence-activated cell sorting and it was shown that the decoys frequently failed reach the cell surface despite intracellular expression. Sensitivity to TRAIL-mediated apoptosis was correlated with cFLIP expression.
88. Tschopp J., Irmler M., Thome M. Inhibition of fas death signals by FLIPs. Curr Opin Immunol. 10:1998;552-558.
89. Irmler M., Thome M., Hahne M., Schneider P., Hofman K., Steiner V., Bodmer J.L., Schroter M., Burns K., Mattmann C.et al. Inhibition of death receptor signals by cellular FLIP. Nature. 388:1997;190-195.
90. Algeciras-Schimnich A., Griffith T.S., Lynch D.H., Paya C.V. Cell cycle-dependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis. J Immunol. 162:1999;5205-5211.
91. Inaba M., Kurasawa K., Mamura M., Kumano K., Saito Y., Iwamoto I. Primed T cells are more resistant to Fas-mediated activation-induced cell death than naive T cells. J Immunol. 163:1999;1315-1320.
92. Perlman H., Pagliari L.J., Georganas C., Mano T., Walsh K., Pope R.M. FLICE-inhibitory protein expression during macrophage differentiation confers resistance to fas-mediated apoptosis. J Exp Med. 190:1999;1679-1688.
93. Wang J., Lobito A.A., Shen F., Hornung F., Winoto A., Lenardo M.J. Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP. Eur J Immunol. 30:2000;155-163.
94. Scaffidi C., Schmitz I., Krammer P.H., Peter M.E. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem. 274:1999;1541-1548.
95. Van Parijs L., Refaeli Y., Abbas A.K., Baltimore D. Autoimmunity as a consequence of retrovirus-mediated expression of c-FLIP in lymphocytes. Immunity. 11:1999;763-770. This report describes the ex vivo transfection of lymphocytes with a bicistronic retroviral vector expressing cFLIP and GFP (green fluorescent protein). Cells were transferred to irradiated mice and GFP-expressing cells were followed. Normal T/B development, normal thymocyte responses to staphylococcal enterotoxin B (SEB), normal activation but a defect in peripheral deletion in response to SEB and the development of autoimmunity resulted.
96. Refaeli Y., Van Parijs L., London C.A., Tschopp J., Abbas A.K. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity. 8:1998;615-623. A study looking for the mechanism of increased sensitivity to Fas induced by IL-2. They demonstrate FasL upregulation and downregulation of cFLIP.
97. Irmler M., Thome M., Hahne M., Schneider P., Hofmann K., Steiner V., Bodmer J.L., Schroter M., Burns K., Mattmann C.et al. Inhibition of death receptor signals by cellular FLIP. Nature. 388:1997;190-195.
98. Kataoka T., Schroter M., Hahne M., Schneider P., Irmler M., Thome M., Froelich C.J., Tschopp J. FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J Immunol. 161:1998;3936-3942.
99. •].
100. •] underline the importance of death receptors such as Fas in tumour immune surveillance. Tumour expression of cFLIP leads to a more aggressive phenotype.