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.