CD19 regulates positive selection and maturation in B lymphopoiesis: lack of CD19 imposes developmental arrest of immature B cells and consequential stimulation of receptor editing.
Ligand-independent signals that are produced by the B-cell antigen receptor (BCR) confer an important positive selection checkpoint for immature B cells. Generation of inappropriate signals imposes developmental arrest of immature B cells, though the fate of these cells has not been investigated. Studies have shown that the lack of CD19 results in inappropriate signaling. In immunoglobulin transgenic mice, this inappropriate signaling impairs positive selection and stimulates receptor editing. Here, we studied the extent and significance of receptor editing in CD19-regulated positive selection of normal, nontransgenic B lymphopoiesis, using our bone marrow culture system. We found that the lack of CD19 resulted in elevated tonic signaling and impaired maturation, as revealed by surface marker expression and by functional assays. Immature CD19-/- B cells did not suppress RAG and underwent intensive receptor editing attempts in culture. Finally, in vivo analysis of light-chain isotype expression and Jkappa use in CD19-/- mice validated our in vitro observations. Our results suggest that CD19 has an important function in regulating positive selection and maturation of nontransgenic B-cell precursors and that receptor editing is an important salvage mechanism for immature B cells that fail positive selection.
Diamant
Eran
E
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Keren
Zohar
Z
Melamed
Doron
D
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002478:Cells, Cultured; D018925:Chemokines / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D017393:RNA Editing / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D018941:Antigens, CD19; D018925:Chemokines; D018398:Homeodomain Proteins; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D008024:Ligands; D008070:Lipopolysaccharides; C064658:RAG-1 protein