Reduction of Thymocyte Numbers in Transgenic Mice Expressing Viral FLICE-Inhibitory Protein in a Fas-Independent Manner

Takahiro Ohyama; Shin-ichi Tsukumo; Nobuyuki Yajima; Kazuhiro Sakamaki; Shin Yonehara

Takahiro Ohyama, Shin-ichi Tsukumo, Nobuyuki Yajima, Kazuhiro Sakamaki, Shin Yonehara

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Keywords: FLIP, Fas, Apoptosis, Thymocyte

JOURNAL FREE ACCESS

2000 Volume 44 Issue 4 Pages 289-297

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Published: April 20, 2000 Received: January 28, 2000 Available on J-STAGE: March 17, 2008 Accepted: February 01, 2000 Advance online publication: - Revised: -
Correction information
Date of correction: March 17, 2008 Reason for correction: - Correction: ABSTRACT Details: Wrong : A viral FLIP (FLICE/caspase-8-Inhibitory Protein), equine herpesvirus type 2 E8 protein, has been shown to inhibit Death receptor-induced apoptosis by suppressing the activation of FLICE/caspase-8. We generated transgenic mice specifically expressing E8 in thymocytes under the control of lck-proximal promoter. Although E8-expressing thymocytes were resistant to Fas-mediated apoptosis, the total number of thymocytes in 4-8-week-old E8 transgenic mice was more than 3-fold less than that in control littermates. This reduction was also observed in E8 transgenic mice with a Fas^-/- background suggesting the reduction to be independent of Fas. The thymocytes of the transgenic mice, however, could similarly respond to CD3-mediated stimulation, indicating that the reduction of thymocyte numbers might be independent of T cell receptor complex-mediated stimulation. Thus, the Death receptor-mediated signaling pathway is too complex to be regarded as only an executor for apoptosis.
Right : A viral FLIP (FLICE/caspase-8-Inhibitory Protein), equine herpesvirus type 2 E8 protein, has been shown to inhibit Death receptor-induced apoptosis by suppressing the activation of FLICE/caspase-8. We generated transgenic mice specifically expressing E8 in thymocytes under the control of lck-proximal promoter. Although E8-expressing thymocytes were resistant to Fas-mediated apoptosis, the total number of thymocytes in 4-8-week-old E8 transgenic mice was more than 3-fold less than that in control littermates. This reduction was also observed in E8 transgenic mice with a Fas-/- background suggesting the reduction to be independent of Fas. The thymocytes of the transgenic mice, however, could similarly respond to CD3- mediated stimulation, indicating that the reduction of thymocyte numbers might be independent of T cell receptor complex-mediated stimulation. Thus, the Death receptor-mediated signaling pathway is too complex to be regarded as only an executor for apoptosis.

Date of correction: March 17, 2008 Reason for correction: - Correction: DTPUB Details: Right : 20000420

Date of correction: March 17, 2008 Reason for correction: - Correction: CITATION Details: Wrong : 1) Alam, A., Cohen, L.Y., Aouad, S., and Sekaly, R.P. 1999. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J. Exp. Med. 190: 1879-1890.
2) Bertin, J., Armstrong, R.C., Ottilie, S., Martin, D.A., Wang, Y., Banks, S., Wang, G.H., Senkevich, T.G., Alnemri, E.S., Moss, B., Lenardo, M.J., Tomaselli, K.J., and Cohen, J.I. 1997. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc. Natl. Acad. Sci. U.S.A. 94: 1172-1176.
3) Boldin, M.P., Goncharov, T.M., Goltsev, Y.V., and Wallach, D. 1996. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85: 803-815.
4) Boldin, M.P., Varfolomeev, E.E., Pancer, Z., Mett, I.L., Camonis, J.H., and Wallach, D. 1995. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270: 7795-7798.
5) Chaffin, K.E., Beals, C.R., Wilkie, T.M., Forbush, K.A., Simon, M.I., and Perlmutter, R.M. 1990. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 9: 3821-3829.
6) Chaudhary, P.M., Jasmin, A., Eby, M.T., and Hood, L. 1999. Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18: 5738-5746.
7) Chinnaiyan, A.M., O'Rourke, K., Tewari, M., and Dixit, V.M. 1995. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81: 505-512.
8) Fehling, H.J., and von Boehmer, H. 1997. Early alpha beta T cell development in the thymus of normal and genetically altered mice. Curr. Opin. Immunol. 9: 263-275.
9) Fernandes-Alnemri, T., Armstrong, R.C., Krebs, J., Srinivasula, S.M., Wang, L., Bullrich, F., Fritz, L.C., Trapani, J.A., Tomaselli, K.J., Litwack, G., and Alnemri, E.S. 1996. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc. Natl. Acad. Sci. U.S.A. 93: 7464-7469.
10) Goltsev, Y.V., Kovalenko, A.V., Arnold, E., Varfolomeev, E.E., Brodianskii, V.M., and Wallach, D. 1997. CASH, a novel caspase homologue with death effector domains. J. Biol. Chem. 272: 19641-19644.
11) Han, D.K., Chaudhary, P.M., Wright, M.E., Friedman, C., Trask, B.J., Riedel, R.T., Baskin, D.G., Schwartz, S.M., and Hood, L. 1997. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BcIXL and initiates cell death. Proc. Natl. Acad. Sci. U.S.A. 94: 11333-11338.
12) Hara, T., and Miyajima, A. 1992. Two distinct functional high affinity receptors for mouse interleukin-3 (IL-3). EMBO J. 11: 1875-1884.
13) Hu, S., Vincenz, C., Buller, M., and Dixit, V.M. 1997. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J. Biol. Chem. 272: 9621-9624.
14) Hu, S., Vincenz, C., Ni, J., Gentz, R., and Dixit, V.M. 1997. I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. J. Biol. Chem. 272: 17255-17257.
15) Inohara, N., Koseki, T., Hu, Y., Chen, S., and Nunez, G. 1997. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc. Natl. Acad. Sci. U.S.A. 94: 10717-10722.
16) Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J.L., Schroter, M., Burns, K., Mattmann, C., Rimoldi, D., French, L.E., and Tschopp, J. 1997. Inhibition of death receptor signals by cellular FLIP [see comments]. Nature 388: 190-195.
17) Itoh, N., Yonehara, S., Ishii, A., Yonehara, M., Mizushima, S., Sameshima, M., Hase, A., Seto, Y., and Nagata, S. 1991. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66: 233-243.
18) Kennedy, N.J., Kataoka, T., Tschopp, J., and Budd, R.C. 1999. Caspase activation is required for T cell proliferation. J. Exp. Med. 190: 1891-1896.
19) Kidd, V.J. 1998. Proteolytic activities that mediate apoptosis. Annu. Rev. Physiol. 60: 533-573.
20) Muzio, M., Chinnaiyan, A.M., Kischkel, F.C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J.D., Zhang, M., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E., and Dixit, V.M. 1996. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85: 817-827.
21) Newton, K., Harris, A.W., Bath, M.L., Smith, K.G.C., and Strasser, A. 1998. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17: 706-718.
22) Nishimura, Y., Ishii, A., Kobayashi, Y., Yamasaki, Y., and Yonehara, S. 1995. Expression and function of mouse Fas antigen on immature and mature T cells. J. Immunol. 154: 4395-4403.
23) Pullen, A.M., Marrack, P., and Kappler, J.W. 1988. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature 335: 796-801.
24) Roths, J.B., Murphy, E.D., and Eicher, E.M. 1984. A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice. J. Exp. Med. 159: 1-20.
25) Senju, S., Negishi, I., Motoyama, N., Wang, F., Nakayama, K.I., Nakayama, K., Lucas, P.J., Hatakeyama, S., Zhang, Q., Yonehara, S., and Loh, D.Y. 1996. Functional significance of the Fas molecule in naive lymphocytes. Int. Immunol. 8: 423-431.
26) Shu, H.B., Halpin, D.R., and Goeddel, D.V. 1997. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 6: 751-763.
27) Singer, G.G., Carrera, A.C., Marshak-Rothstein, A., Martinez, C., and Abbas, A.K. 1994. Apoptosis, Fas and systemic autoimmunity: the MRL-lpr/lpr model. Curr. Opin. Immunol. 6: 913-920.
28) Smith, K.G., Strasser, A., and Vaux, D.L. 1996. CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J. 15: 5167-5176.
29) Srinivasula, S.M., Ahmad, M., Ottilie, S., Bullrich, F., Banks, S., Wang, Y., Fernandes-Alnemri, T., Croce, C.M., Litwack, G., Tomaselli, K.J., Armstrong, R.C., and Alnemri, E.S. 1997. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J. Biol. Chem. 272: 18542-18545.
30) Steinberg, A.D., Roths, J.B., Murphy, E.D., Steinberg, R.T., and Raveche, E.S. 1980. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J. Immunol. 125: 871-873.
31) Surh, C.D., and Sprent, J. 1994. T-cell apoptosis detected in situ during positive and negative selection in the thymus [see comments]. Nature 372: 100-103.
32) Thome, M., Schneider, P., Hofmann, K., Fickenscher, H., Meinl, E., Neipel, F., Mattmann, C., Burns, K., Bodmer, J.L., Schroter, M., Scaffidi, C., Krammer, P.H., Peter, M.E., and Tschopp, J. 1997. Viral FLICE-inhibitory proteins (FLIPS) prevent apoptosis induced by death receptors. Nature 386: 517-521.
33) Van Parijs, L., Refaeli, Y., Abbas, A.K., and Baltimore, D. 1999. Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes [In Process Citation]. Immunity 11: 763-770.
34) Wajant, H., Johannes, F.J., Haas, E., Siemienski, K., Schwenzer, R., Schubert, G., Weiss, T., Grell, M., and Scheurich, P. 1998. Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2- mediated cell death but not gene induction. Curr. Biol. 8: 113-116.
35) Wallach, D., Varfolomeev, E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., and Boldin, M.P. 1999. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17: 331-367.
36) Walsh, C.M., Wen, B.G., Chinnaiyan, A.M., O'Rourke, K., Dixit, V.M., and Hedrick, S.M. 1998. A role for FADD in T cell activation and development. Immunity 8: 439-449.
37) Yeh, W.C., Pompa, J.L., McCurrach, M.E., Shu, H.B., Elia, A.J., Shahinian, A., Ng, M., Wakeham, A., Khoo, W., Mitchell, K., El-Deiry, W.S., Lowe, S.W., Goeddel, D.V., and Mak, T.W. 1998. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279: 1954-1958.
38) Yonehara, S., Ishii, A., and 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: 1747-1756.
39) Zhang, J., Cado, D., Chen, A., Kabra, N.H., and Winoto, A. 1998. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mortl. Nature 392: 296-300.

Right : 1) Alam, A., Cohen, L.Y., Aouad, S., and Sekaly, R.P. 1999. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J. Exp. Med. 190 : 1879-1890.
2) Bertin, J., Armstrong, R.C., Ottilie, S., Martin, D.A., Wang, Y., Banks, S., Wang, G.H., Senkevich, T.G., Alnemri, E.S., Moss, B., Lenardo, M.J., Tomaselli, K.J., and Cohen, J.I. 1997. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc. Natl. Acad. Sci. U.S.A. 94 : 1172-1176.
3) Boldin, M.P., Goncharov, T.M., Goltsev, Y.V., and Wallach, D. 1996. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85 : 803-815.
4) Boldin, M.P., Varfolomeev, E.E., Pancer, Z., Men, I.L., Camonis, J.H., and Wallach, D. 1995. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270 : 7795-7798.
5) Chaffin, K.E., Beals, C.R., Wilkie, T.M., Forbush, K.A., Simon, M.I., and Perlmutter, R.M. 1990. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 9 : 3821-3829.
6) Chaudhary, P.M., Jasmin, A., Eby, M.T., and Hood, L. 1999. Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18 : 5738-5746.
7) Chinnaiyan, A.M., O'Rourke, K., Tewari, M., and Dixit, V.M. 1995. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81 : 505-512.
8) Fehling, H.J., and von Boehmer, H. 1997. Early alpha beta T cell development in the thymus of normal and genetically altered mice. Curr. Opin. Immunol. 9 : 263-275.
9) Fernandes-Alnemri, T., Armstrong, R.C., Krebs, J., Srinivasula, S.M., Wang, L., Bullrich, E, Fritz, L.C., Trapani, J.A., Tomaselli, K.J., Litwack, G., and Alnemri, E.S. 1996. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc. Natl. Acad. Sci. U.S.A. 93 : 7464-7469.
10) Goltsev, Y.V., Kovalenko, A.V., Arnold, E., Varfolomeev, E.E., Brodianskii, V.M., and Wallach, D. 1997. CASH, a novel caspase homologue with death effector domains. J. Biol. Chem. 272 : 19641-19644.
11) Han, D.K., Chaudhary, P.M., Wright, M.E., Friedman, C., Trask, B.J., Riedel, R.T., Baskin, D.G., Schwartz, S.M., and Hood, L. 1997. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc. Natl. Acad. Sci. U.S.A. 94 : 11333-11338.
12) Hara, T., and Miyajima, A. 1992. Two distinct functional high affinity receptors for mouse interleukin-3 (IL-3). EMBO J. 11 : 1875-1884.
13) Hu, S., Vincenz, C., Buller, M., and Dixit, V.M. 1997. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J. Biol. Chem. 272 : 9621-9624.
14) Hu, S., Vincenz, C., Ni, J., Gentz, R., and Dixit, V.M. 1997. I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. J. Biol. Chem. 272 : 17255-17257.
15) Inohara, N., Koseki, T., Hu, Y., Chen, S., and Nunez, G. 1997. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc. Natl. Acad. Sci. U.S.A. 94 : 10717-10722.
16) Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J.L., Schroter, M., Burns, K., Mattmann, C., Rimoldi, D., French, L.E., and Tschopp, J. 1997. Inhibition of death receptor signals by cellular FLIP [see comments]. Nature 388 : 190-195.
17) Itoh, N., Yonehara, S., Ishii, A., Yonehara, M., Mizushima, S., Sameshima, M., Hase, A., Seto, Y., and Nagata, S. 1991. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66 : 233-243.
18) Kennedy, N.J., Kataoka, T., Tschopp, J., and Budd, R.C. 1999. Caspase activation is required for T cell proliferation. J. Exp. Med. 190 : 1891-1896.
19) Kidd, V.J. 1998. Proteolytic activities that mediate apoptosis. Annu. Rev. Physiol. 60 : 533-573.
20) Muzio, M., Chinnaiyan, A.M., Kischkel, F.C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J.D., Zhang, M., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E., and Dixit, V.M. 1996. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85 : 817-827.
21) Newton, K., Harris, A.W., Bath, M.L., Smith, K.G.C., and Strasser, A. 1998. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17 : 706-718.
22) Nishimura, Y., Ishii, A., Kobayashi, Y., Yamasaki, Y., and Yonehara, S. 1995. Expression and function of mouse Fas antigen on immature and mature T cells. J. Immunol. 154 : 4395-4403.
23) Pullen, A.M., Marrack, P., and Kappler, J.W. 1988. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature 335 : 796-801.
24) Roths, J.B., Murphy, E.D., and Eicher, E.M. 1984. A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice. J. Exp. Med. 159 : 1-20.
25) Senju, S., Negishi, I., Motoyama, N., Wang, F., Nakayama, K.I., Nakayama, K., Lucas, P.J., Hatakeyama, S., Zhang, Q., Yonehara, S., and Loh, D.Y. 1996. Functional significance of the Fas molecule in naive lymphocytes. Int. Immunol. 8 : 423-431.
26) Shu, H.B., Halpin, D.R., and Goeddel, D.V. 1997. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 6 : 751-763.
27) Singer, G.G., Carrera, A.C., Marshak-Rothstein, A., Martinez, C., and Abbas, A.K. 1994. Apoptosis, Fas and systemic autoimmunity : the MRL-lpr/lpr model. Curr. Opin. Immunol. 6 : 913-920.
28) Smith, K.G., Strasser, A., and Vaux, D.L. 1996. CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1) -transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J. 15 : 5167-5176.
29) Srinivasula, S.M., Ahmad, M., Ottilie, S., Bullrich, F., Banks, S., Wang, Y., Fernandes-Alnemri, T., Croce, C.M., Litwack, G., Tomaselli, K.J., Armstrong, R.C., and Alnemri, E.S. 1997. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J. Biol. Chem. 272 : 18542H 8545.
30) Steinberg, A.D., Roths, J.B., Murphy, E.D., Steinberg, R.T., and Raveche, E.S. 1980. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J. Immunol. 125 : 871-873.
31) Surh, C.D., and Sprent, J. 1994. T-cell apoptosis detected in situ during positive and negative selection in the thymus [see comments]. Nature 372 : 100-103.
32) Thome, M., Schneider, P., Hofmann, K., Fickenscher, H., Meinl, E., Neipel, F., Mattmann, C., Burns, K., Bodmer, J.L., Schroter, M., Scaffidi, C., Krammer, P.H., Peter, M.E., and Tschopp, J. 1997. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386 : 517-521.
33) Van Parijs, L., Refaeli, Y., Abbas, A.K., and Baltimore, D. 1999. Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes [In Process Citation]. Immunity 11 : 763-770.
34) Wajant, H., Johannes, F.J., Haas, E., Siemienski, K., Schwenzer, R., Schubert, G., Weiss, T., Grell, M., and Scheurich, P. 1998. Dominant-negative FADD inhibits TNFR60-, Fas/Apol- and TRAIL-R/Apo2- mediated cell death but not gene induction. Curr. Biol. 8 : 113-116.
35) Wallach, D., Varfolomeev, E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., and Boldin, M.P. 1999. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17 : 331-367.
36) Walsh, C.M., Wen, B.G., Chinnaiyan, A.M., O'Rourke, K., Dixit, V.M., and Hedrick, S.M. 1998. A role for FADD in T cell activation and development. Immunity 8 : 439-449.
37) Yeh, W.C., Pompa, J.L., McCurrach, M.E., Shu, H.B., Elia, A.J., Shahinian, A., Ng, M., Wakeham, A., Khoo, W., Mitchell, K., El-Deiry, W.S., Lowe, S.W., Goeddel, D.V., and Mak, T.W. 1998. FADD : essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279 : 1954-1958.
38) Yonehara, S., Ishii, A., and 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 : 1747-1756.
39) Zhang, J., Cado, D., Chen, A., Kabra, N.H., and Winoto, A. 1998. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort 1. Nature 392 : 296-300.

Abstract

A viral FLIP (FLICE/caspase-8-Inhibitory Protein), equine herpesvirus type 2 E8 protein, has been shown to inhibit Death receptor-induced apoptosis by suppressing the activation of FLICE/caspase-8. We generated transgenic mice specifically expressing E8 in thymocytes under the control of lck-proximal promoter. Although E8-expressing thymocytes were resistant to Fas-mediated apoptosis, the total number of thymocytes in 4-8-week-old E8 transgenic mice was more than 3-fold less than that in control littermates. This reduction was also observed in E8 transgenic mice with a Fas-/- background suggesting the reduction to be independent of Fas. The thymocytes of the transgenic mice, however, could similarly respond to CD3- mediated stimulation, indicating that the reduction of thymocyte numbers might be independent of T cell receptor complex-mediated stimulation. Thus, the Death receptor-mediated signaling pathway is too complex to be regarded as only an executor for apoptosis.

Corresponding author

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