|M.Sc Student||Keren Zohar|
|Subject||Modulation of B Cell Receptor Tonic Signals Regulates|
Positive Selection and Receptor Editing in
Immature B Lymphocyte
|Department||Department of Medicine||Supervisor||Professor Doron Melamed|
Maturation of B-lymphocyte 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 edition, maturation of non-self B cells and migration to the spleen, a process referred 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 block positive selection but also activates receptor editing. In 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 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 found significantly reduced levels in phosphorylation of the inhibitory protein DOK in immature 3-83Tg CD19-/- B cells, suggesting that increased basal signals in these cells results from reduced inhibitory balancing activity. We also show that positive selection and developmental progression from the bone marrow to the spleen is limited to cells capable to establish appropriate tonic signals, as in contrast to immature cells, splenic 3-83Tg B cells deficient of CD19 have similar BCR tonic signals as the control 3-83Tg cells. This development progression is accompanied with activation of molecules signaling for growth and survival like ERK. Hence, we suggest that ligand-independent BCR tonic signals are required for promoting positive selection and to suppress the receptor editing mechanism in immature B cells.