SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-3 (STAT3) IS CONSTITUTIVELY ACTIVATED IN NORMAL, SELF-RENEWING B-1 CELLS BUT ONLY INDUCIBLY EXPRESSED IN CONVENTIONAL B-LYMPHOCYTES

Cytokine and growth factor receptor engagement leads to the rapid phos phorylation and activation of latent, cytosolic signal transducers and activators of transcription (STAT) proteins, which then translocate t o the nucleus where they regulate transcriptional events from specific promoter sequences. STAT3 expression in particular has been associate d with Abl, Src, and HTLV-1 transformation of normal cells. B-1 lympho cytes are self-renewing, CD5(+) B cells that display a propensity for malignant transformation and are the normal counterpart to human chron ic lymphocytic leukemias. Further, B-1 cells are characterized by aber rant intracellular signaling, including hyperresponsiveness to phorbol ester PKC agonists. Here we demonstrate that B-1 lymphocytes constitu tively express nuclear activated STAT3, which is not expressed by unma nipulated conventional (B-2) lymphocytes. In contrast, STAT3 activatio n is induced in B-2 cells after antigen receptor engagement in a delay ed fashion (after 3 h). Induction of STAT3 is inhibited by both the se rine/threonine protein kinase inhibitor H-7 and the immunosuppressive drug rapamycin and requires de novo protein synthesis, demonstrating n ovel coupling between sig and STAT proteins that differs from the clas sical paradigm for STAT induction by cytokine receptors. The inability of prolonged stimulation of conventional B-2 cells with anti-Ig, a tr eatment sufficient to induce CD5 expression, to result in sustained ST AT3 activation suggests that STAT3 is a specific nuclear marker for B- 1 cells. Thus, STAT3 may play a role in B cell antigen-specific signal ing responses, and its constitutive activation is associated with a no rmal cell population exhibiting intrinsic proliferative behavior.