Abstract
When murine B-lymphoma cells are activated by crosslinking their membrane IgM receptors, they show evanescent myc transcription, growth arrest mediated by an increase in p27, and then undergo programmed cell death. Our laboratory has previously shown that the initiation of this process requires the activation of src-family protein tyrosine kinases (PTK) via their association with the ITAM (Immunoreceptor Tyrosine Activation Motif) in the Ig-associated proteins, Igα and Igβ. While PTK activation is required for growth arrest and apoptosis, it is not sufficient since mutation of critical tyrosines in the ITAM may allow for initial phosphorylation events, but no apoptosis. To explore the role of these kinases in apoptosis, we transfected both T cell and B cell lymphomas with CD8-PTK chimeric fusion proteins and found that only CD8-syk crosslinking led to cell death in the A1.1 T cell line; none of the B cell transfectants were responsive to CD8 crosslinking. Interestingly, many of the T cell transfectants showed strong PTK activation, but no measurable biologic response. Thus, initial signaling (chemistry) need not have cellular consequences (biology). To examine the role of c-myc in B cell apoptosis, we used antisense for c-myc and found that it prevented the loss of message for this oncogene and blocked apoptosis; antisense oligos for p27 also blocked cell cycle arrest and apoptosis. Interestingly, treatment of B cell lymphomas with dexamethasone augmented apoptosis induced by receptor crosslinking, whereas it blocked anti-TCR-mediated apoptosis in T cells. We propose that myc is critically regulated by dexamethasone in establishing the responsiveness of T versus B cell lines. In addition, receptor crosslinking led to FasL expression and suicide in T cell lines but not in B lymphomas. Although B cells are sensitive to Fas-mediated death, anti-IgM-driven B cell apoptosis appears to be Fas-independent. These data suggest that T and B cell apoptosis may be independently regulated to maintain the integrity of the immune system, and that myc transcription plays a pivotal role in this process.
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References
Alber, G., Kim, K.-M., Weiser, P., Riesterer, C., Carsetti, R., and Reth, M. 1993 Molecular mimicry of the antigen receptor signaling motif by transmembrane proteins of Epstein-Barr virus and the bovine leukemia virus. Curr. Biol. 3, 333–339.
Ales-Martinez, J-E., Warner, G. and Scott, D.W. 1988. Immunoglobulin D and M mediate signals that are qualitatively different in B cells with an immature phenotype. Proc. Natl. Acad. Sci. USA 85, 6919–6923.
Brunner, T., Mogil, R.J., LaFace, D., Yoo, N.J., Mahboubi, A., Echeverri, F., Martin, J., Force, W.R., Lynch, D.H., Ware, CF., and Green, D.R. 1995. Cell-autonomous Fas (CD95)/Fas-Ligand and interaction mediates activation-induced apoptosis in T cell hybridomas. Nature 373, 441–444.
Burkhardt, A.L., Brunswick, M., Bolen, J.B., and Mond, J.J. 1991. Anti-immunoglobulin stimulation of B lymphocytes activate src-related protein-tyrosine kinases. Proc. Natl. Acad. Sci. USA 88, 7410–7414.
Campbell, M.-A., and Sefton, B.M. 1992. Association between B-lymphocyte membrane immunoglobulin and multiple members of the sre family of protein tyrosine kinases. Mol. Cell. Biol. 12, 2315–2321.
Cleary, A.M., Fortune, S.M., Yellin, M.J., Chess, L., and Lederman, S. 1995. Opposing roles of CD95 (Fas/APO-1) and CD40 in the death and rescue of human low density tonsillar B cells. J. Immunol. 155, 3329–3337.
Dhein, J., Walczak, H., Baümler, C., Debatin, K.-M., and Krammer, P. 1995. Autocrine T-cell suicide mediated by APO-1 (Fas/CD95). Nature 373, 438–441.
Ezhevsky, S.A., Toyoshima, H., Hunter, T., and Scott, D.W. 1996. Role of cyclin A and p27 in anti-IgM-induced Gl growth arrest of murine B-cell lymphomas. Mol. Biol. Cell 7, 553–564.
Fisher, G., Kent, S.C., Joseph, L., Green, D.R., and Scott, D.W. 1994. Lymphoma models for B cell activation and tolerance. X. Anti-μ-mediated growth arrest and apoptosis of murine B cell lymphomas is prevented by the stabilization of myc. J. Exp. Med. 179, 221–228.
Flaswinkel, H., and Reth, M. 1994. Dual role of the tyrosine activation motif of the Ig-α protein during signal transduction via the B cell antigen receptor. EMBO J. 13, 83–89.
Garrone, P., Neidhardt, E.-M., Garcia, E., Galibert, L., van Kooten, C., and Banchereau, J. 1995. Fas ligation induces apoptosis of CD-40-activated human B lymphocytes. J. Exp. Med. 182, 1265–1273.
Han, S., Zheng, B., Dal Porto, J., and Kelsoe, G. 1995. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl) acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J. Exp. Med. 182, 1635–1644.
Heath, A.W., Wu, W.W., and Howard, M.C. 1994. Monoclonal antibodies to murine CD40 define two distinct functional epitopes. Eur. J. Immun. 24, 1828–1834.
Hombach, J., Leclercq, L., Radbruch, A., Rajewsky, K., and Reth, M. 1988. A novel 34-kDa protein co-isolated with the IgM molecule in surface IgM expressing cells. EMBO J. 7, 3451–3456.
Hutchcroft, J.E., Harrison, M.L., and Geahlen, R.L. 1992. Association of the 72-kDa protein tyrosine kinase PTK72 with the B cell antigen receptor. J. Biol. Chem. 267, 8613–8619.
Joseph, L.F., Ezhevsky, S., and Scott, D.W. 1995. Lymphoma model for B-cell activation and tolerance: Anti-immunoglobulin M treatment induces growth arrest by preventing the formation of an active kinase complex which phosphorylates retinoblastoma gene product in G1. Cell Growth & Differentiation 6, 51–57.
Ju, S.-T., Panka, D., Cui, H., Ettinger, R., el-Khatib, M., Sherr, D., Stanger, B.Z., and Marshak-Rothstein, A. 1995. Fas (CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373, 444–448.
Krieg, A.M., Yi, A-K., Maison, S., Waldschmidt, T.J., Bishop, G.A., Teasdale, R., Koretzky, G.A., and Klinman, D.M. 1995. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549.
Lagresle, C., Bella, C., Daniel, P.T., Krammer, P., and DeFrance, T. 1995. Regulation of germinal center B cell differentiation. Role of the human APO-1/Fas (CD95) molecule. J. Immunol. 154, 5746–5756.
Lin, J., and Justement, L.B. 1992. The mb-l/b29 heterodimer couples the B cell antigen receptor to multiple src family protein tyrosine kinases. J. Immunol. 149, 1548–1555.
Maheswaran, S., McCormack, J.E., and Sonenshein, G.E. 1993. Changes in phosphorylation of myc oncogene and RB antioncogene protein products during growth arrest of the murine lymphoma WEHI 231 cell line. Oncogene 6, 1965–1971.
Mandik, L., Nguyen, K.-A.T., and Erickson, J. 1995. Fas expression on B lineage cells. Eur. J. Immunol. 25, 3148–3154.
McCormack, J.E., Pepe, V.H., Kent, R.B., Dean, M., Marshak-Rothstein, A., and Sonenshein, G.E. 1984. Specific regulation of c-myc oncogene expression in a murine B-cell lymphoma. Proc. Natl. Acad. Sci, USA 81, 5546–5550.
Onel, K.B., Tucek-Szabo, C.L., Ashany, D., Lacy, E., Nikolic-Zugic, J., and Elkon, K.B. 1995. Expression and function of the murine CD95/FasR/APO-l receptor in relation to B cell ontogeny. Eur. J. Immunol. 25, 2940–2947.
Pennell, C.A., and Scott, D.W. 1986a. Models and mechanisms for signal transduction in B cells. Immunol. Res. 5, 61–70.
Pennell, C.A., and Scott, D.W. 1986b. Lymphoma models for B cell activation and tolerance. IV. Growth inhibition by anti-Ig of CH31 and CH33 B-lymphoma cells. Eur. J. Immunol. 16, 1577–1581.
Pleiman, CM., Abrams, C., Gauen, L.T., Bedzyk, W., Jongstra, J., Shaw, A.S., and Cambier, J.C. 1994. Distinct p53/p56lyn” and p59fyn domains associate with non-phosphorylated and phosphorylated Ig-α. Proc. Natl. Acad. Sci. USA 91, 4268–4272.
Rathmell, J.C., Cooke, M.P., Ho, W., Grein, J., Townsend, S., Davis, M.M., and Goodnow, C. 1995. CD95 (fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature 376, 181–183.
Reth, M. 1989. Antigen receptor tail clue. Nature 338, 383–384.
Rothstein, T.L., Wang, J. K., Panka, D.J., Foote, L.C., Wang, Z., Stanger, B., Cui, H., Ju, S.T., and Marshak-Rothstein, A. 1995. Protection against Fas-dependent TH1-mediated apoptosis by antigen receptor engagement in B cells. Nature 374, 163–165.
Sakaguchi, N., Kashiwamura, S., Kimoto, M., Thalmann, P., and Melchers, F. 1988. B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties. EMBO J. 7, 3457–3464.
Scheuermann, R.H., Racila, E., Tucker, T., Yefenof, E., Street, N.E., Vitetta, E. S., Picker, L.J., and Uhr, J.W. 1994. Lyn tyrosine kinase signals cell cycle arrest but not apoptosis in B-lineage lymphoma cells. Proc. Natl. Acad. Sci. USA 91, 4048–4052.
Scott, D.W., Livnat, D., Pennell, C.A., and Keng, P. 1986. Lymphoma models for B cell activation and tolerance. III. Cell cycle dependence for negative signaling of WEHI-231 B lymphoma cells by anti-μ. J. Exp. Med. 164, 156–164.
Scott, D.W., Ezhevsky, S., Maddox, B., Washart, K., Yao, X., and Shi, Y. 1995. Scenes from a short life: Checkpoints and progression signals for immature B-cell life versus apoptosis. In: Lymphocyte Signalling (ed. K. Rigley and M. Harnett), John Wiley, Chichester, England, pp. 167–181.
Scott, D., Grdina, T., and Y. Shi. 1996. T cells commit suicide, but B cells are murdered. J. Immunol. 156, 2352–2356.
Shi, Y., Glynn, M., Guilbert, L.J., Cotter, T.G., Bissonette, R.P., and Green, D.R. 1992. Role for c-myc in activation induced apoptotic cell death in T-cell hybridoma. Science 257, 212–214.
Smith, K.G.C., Nossal, G.J.V., and Tarlinton, D.M. 1995. Fas is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen. Proc. Nat’l. Acad. Sci., USA 92, 11628–11632.
Tisch, R., Roifman, CM., and Hozumi, N. 1988. Functional differences between immunoglobulins M and D are expressed on the surface of an immature B-cell line. Proc. Natl. Acad. Sci, USA 85, 6914–6918.
Valentine, M.A., and Licciardi, K.A. 1992. Rescue from anti-IgM-induced programmed cell death by the B cell surface proteins CD20 and CD40. Eur. J. Immunol. 22, 3141–3148.
Warner, G.L., Ludlow, J., Nelson, D.O., Gaur, A., and Scott, D.W. 1992 Anti-immunoglobulin treatment of B cell lymphomas induce active TGF-β but pRB hypophosphorylation is TGF-β independent. Cell Growth Differ. 3, 175–181.
Warner, G.L., Nelson, D., and Scott, D.W. 1992. Synergy between TGF-beta and anti-IgM in growth inhibition of CD5+ B cell lymphomas. Ann. N. Y Acad. Sci. 651, 274–276.
Wu, M., Arsura, M., Bella, R., Fitzgerald, M., Lee, H., Schauer, S., Sherr, D., and Sonenshein, G. 1996. Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells. Molec. Cell. Biol. 16, 5015–5025.
Yamanashi, Y, Kakiuchi, T., Mizuguchi, J., Yamamoto, T., and Toyoshima, K. 1991. Association of B cell antigen receptor with protein tyrosine kinase Lyn. Science 251, 192–194.
Yao, X., and Scott, D.W. 1993a. Antisense oligodeoxynucleotides to blk gene prevents anti-μ-induced growth inhibition and apoptosis in a B-cell lymphoma. Proc. Natl. Acad. Sci. USA 90, 7964–7968.
Yao, X., and Scott, D.W. 1993b. Expression of protein tyrosine kinases in the Ig complex of anti-μ-sensitive and anti-μ-resistant B-cell lymphomas: Role of the p55blk kinase in signaling growth arrest and apoptosis. Immunol. Rev. 132, 163–186.
Yao, X., Flaswinkel, H., Reth, M., and Scott, D.W. 1995. Immunoreceptor tyrosine-based activation motif is required to signal pathways of receptor-mediated growth arrest and apoptosis in murine B lymphoma cells. J. Immunol. 155, 652–661.
Zacharchuk, C.M., Mercep, M., Chakraborti, P.K., Simons, S.S., and Ashwell, J.D. 1990. Programmed T lymphocyte death. Cell activation-and steroid-induced pathways are mutually antagonistic. J. Immunol. 145, 4037–4045.
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Scott, D.W. et al. (1997). Murder and Suicide. In: Shi, YB., Shi, Y., Xu, Y., Scott, D.W. (eds) Programmed Cell Death. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0072-2_10
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DOI: https://doi.org/10.1007/978-1-4899-0072-2_10
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