Murder and Suicide
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.
KeywordsGrowth Arrest Germinal Center Protein Tyrosine Kinase Bovine Leukemia Virus Cell Antigen Receptor
Unable to display preview. Download preview PDF.
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.Google Scholar
- 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.Google Scholar
- 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.Google Scholar
- 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.Google Scholar