Cytokine and growth factor receptor engagement leads to the rapid 
phosphorylation and activation of latent, cytosolic signal transducers and 
activators of transcription (STAT) proteins, which then translocate to the 
nucleus where they regulate transcriptional events from specific promoter 
sequences. STAT3 expression in particular has been associated with Abl, Src, and 
HTLV-1 transformation of normal cells. B-1 lymphocytes are self-renewing, CD5+ B 
cells that display a propensity for malignant transformation and are the normal 
counterpart to human chronic lymphocytic leukemias. Further, B-1 cells are 
characterized by aberrant intracellular signaling, including hyperresponsiveness 
to phorbol ester PKC agonists. Here we demonstrate that B-1 lymphocytes 
constitutively express nuclear activated STAT3, which is not expressed by 
unmanipulated conventional (B-2) lymphocytes. In contrast, STAT3 activation is 
induced in B-2 cells after antigen receptor engagement in a delayed fashion 
(after 3 h). Induction of STAT3 is inhibited by both the serine/threonine 
protein kinase inhibitor H-7 and the immunosuppressive drug rapamycin and 
requires de novo protein synthesis, demonstrating novel coupling between sIg and 
STAT proteins that differs from the classical paradigm for STAT induction by 
cytokine receptors. The inability of prolonged stimulation of conventional B-2 
cells with anti-Ig, a treatment sufficient to induce CD5 expression, to result 
in sustained STAT3 activation suggests that STAT3 is a specific nuclear marker 
for B-1 cells. Thus, STAT3 may play a role in B cell antigen-specific signaling 
responses, and its constitutive activation is associated with a normal cell 
population exhibiting intrinsic proliferative behavior.