Abstract
We present evidence that the CD19 receptor is functionally operative and 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 signaling ability of CD19 does not depend on the existence of a functional B-cell antigen receptor complex (ARC). In B-cell precursors (BCP) lacking 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 antibody (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 different intracellular messenger systems. Remarkably, CD19 becomes rapidly phosphorylated on tyrosine residues upon engagement of several other surface receptors as well, suggesting that it may function as a common response element linked via tyrosine phosphorylation to multiple BCP/B-cell receptors and signaling pathways. Furthermore, in all B-lineage lymphoid cell populations, co-approximation of the receptors CD19 and CD72 (ligand for the CD5 T-cell receptor) generates a stronger signal than the engagement of either individual receptor. These convergent observations constitute a strong argument for an important regulatory function of CD19 in human BCP and prompt the hypothesis that the CD19 receptor may play an important role in cognate interactions between B- and T-lineage lymphoid compartments as well as the coordinate production of BCP at multiple stages of human B-cell ontogeny.
Highlights
From the $TumorImmunology Laboratory, Departments of VTherapeuticRadiology-RadiationOncology, §Pediatrics, I(Pharmacology, and **BoneMarrow Transplant Program, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455 and the §#Signal Transduction Laboratory, Department of Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543
The function of CD19 at earlier stages of B-cell development prior to acquisition and expression of a functional antigen receptor complex (ARC) has not been addressed.The results presented here indicate that CD19 possesses the ability totransmit pleiotropic sfgnals independently of other B-cell surface proteins through the activation of associatedPTKs
CD19 appears to be a commonresponse element involved with protein tyrosine kinases (PTK) signaling stimulated through diverse B-lymphocyte surface proteins such as the B-cell antigen receptor, CD40 receptor, and CD72 receptor
Summary
Stages of Hunuzn B-cell Ontogeny-In mature B-lymphocytes as well BCP, stimulation of inositol phospholipid metabolism by activation of phospholipase C represents one of the earliest biochemical events in stimulus-response coupling (Coggeshall et al, 1992; Ledbetter et al, 1988; Uckun andLedbetter, 1988b; Uckun et al, 1991a, 1991b). GEN +aCDl9xCD72 that the CD19 protein lacks endogenous enzymatic activity (Stamenkovic and Seed, 1988; Tedder and Isaacs, 1989), our observation that CD19 is phosphorylated on tyrosine following engagement of various B-cell receptors suggested that it representsasubstrate for one or more B-cell PTKs.To explore the possibility that CD19 might be associated with PTKs, we first examined whether CD19 immunoprecipitates possessed detectable protein kinase activity For these experiments, RAMOS early B-cells were stimulated with anti-IgM, digitonin cell lysates were immunoprecipitatedwith antiCD19mAbB43, and immune complex kinase assays were performed.
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