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J. Biol. Chem., Vol. 279, Issue 14, 13418-13424, April 2, 2004

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Modification of Ligand-independent B Cell Receptor Tonic Signals Activates Receptor Editing in Immature B Lymphocytes^*

Zohar Keren, Eran Diamant, Olga Ostrovsky, Eyal Bengal¶, and Doron Melamed¶||

From the Technion, Faculty of Medicine, Departments of Immunology and Biochemistry, ^¶Rappaport Family Institute for Research in the Medical Sciences, Haifa 31096, Israel

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.

Received for publication, October 31, 2003 , and in revised form, November 19, 2003.

^* This work was supported by the Israel Cancer Research Fund-Rosenwasser Trust, the Israel Ministry of Science jointly with the Deutsches Krebsforschungszentrum (Heidelberg, Germany), the Mars Pittsburgh Foundation for Medical Research, and the Hirshenstrauss-Gutman Medical Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 972-4-829-5237; Fax: 972-4-829-5245; E-mail: melamedd{at}tx.technion.ac.il.

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