Modification of ligand-independent B cell receptor tonic signals activates receptor editing in immature B lymphocytes.
Maturation of B lymphocytes strictly depends on the signaling competence of the B cell antigen receptor (BCR). Autoreactive receptors undergo negative selection and can be replaced by receptor editing. In addition, the process of maturation of non-self B cells and migration to the spleen, referred to as positive selection, is limited by the signaling competence of the BCR. Using 3-83Tg mice deficient of CD19 we have shown that signaling incompetence not only blocks positive selection but also activates receptor editing. Here we study the role of ligand-independent BCR tonic tyrosine phosphorylation signals in activation of receptor editing. We find that editing, immature 3-83Tg B cells deficient of CD19 have elevated BCR tonic signals and that lowering these tonic signals effectively suppresses receptor editing. Furthermore, we show that elevation of BCR tonic signals in non-editing, immature 3-83Tg B cells stimulates significant receptor editing. We also show that positive selection and developmental progression from the bone marrow to the spleen are limited to cells capable of establishing appropriate tonic signals, as in contrast to immature cells, splenic 3-83Tg B cells deficient of CD19 have BCR tonic signals similar to those of the control 3-83Tg cells. This developmental progression is accompanied by activation of molecules signaling for growth and survival. Hence, we suggest that ligand-independent BCR tonic signals are required for promoting positive selection and suppressing the receptor-editing mechanism in immature B cells.
Keren
Zohar
Z
Technion, Faculty of Medicine, Departments of Immunology and Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Haifa 31096, Israel.
Diamant
Eran
E
Ostrovsky
Olga
O
Bengal
Eyal
E
Melamed
Doron
D
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D017393:RNA Editing / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D014443:Tyrosine / Q000378:metabolism
D018941:Antigens, CD19; D008024:Ligands; D014443:Tyrosine