SIGNAL-TRANSDUCTION THROUGH THE CD19 RECEPTOR DURING DISCRETE DEVELOPMENTAL STAGES OF HUMAN B-CELL ONTOGENY

We present evidence that the CD19 receptor is functionally operative a nd transmits pleiotropic signals throughout the pro-B, pre-pre-B, pre- B, early B, and mature B cell stages of human B-cell ontogeny. The sig naling ability of CD19 does not depend on the existence of a functiona l B-cell antigen receptor complex (ARC). In B-cell precursors (BCP) la cking a functional ARC, CD19 is physically and functionally associated with Src family protein tyrosine kinases (PTK). The engagement of the CD19 receptor on BCP with a high affinity anti-CD19 monoclonal antibo dy (mAb) or its homoconjugate rapidly activates the associated PTK and results in tyrosine phosphorylation of CD19. Moreover, this proximal PTK activation step triggers downstream stimulation of several differe nt intracellular messenger systems. Remarkably, CD19 becomes rapidly p hosphorylated on tyrosine residues upon engagement of several other su rface receptors as well, suggesting that it may function as a common r esponse element linked via tyrosine phosphorylation to multiple BCP/B- cell receptors and signaling pathways. Furthermore, in all B-lineage l ymphoid cell populations, co-approximation of the receptors CD19 and C D72 (ligand for the CD5 T-cell receptor) generates a stronger signal t han the engagement of either individual receptor. These convergent obs ervations constitute a strong argument for an important regulatory fun ction of CD19 in human BCP and prompt the hypothesis that the CD19 rec eptor may play an important role in cognate interactions between B- an d T-lineage lymphoid compartments as well as the coordinate production of BCP at multiple stages of human B-cell ontogeny.