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Cutting Edge: Acute and Chronic Exposure of Immature B Cells to Antigen Leads to Impaired Homing and SHIP1-Dependent Reduction in Stromal Cell-Derived Factor-1 Responsiveness¹

Integrated Department of Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, CO 80206

An encounter of B cells with cognate self Ags in the periphery can lead to anergy, a condition characterized by altered anatomical localization, shortened life span, and refractility to Ag stimulation. We recently reported that an immature B cell encounter with cognate self-Ag in the bone marrow can also lead to anergy. In this study we show that anergic as well as acutely Ag-stimulated immature B cells are defective in stromal cell-derived factor-1 (SDF-1)-induced calcium mobilization and migration and do not localize to bone marrow following adoptive transfer. This hyporesponsiveness does not involve CXCR4 modulation. However, BCR signal-mediated hyporesponsiveness to SDF-1 is associated with phosphorylation of the 5-inositol phosphatase SHIP1 and requires SHIP1 expression. Therefore, an encounter with cognate Ag may, by preventing SDF-1-induced phosphatidylinositol 3,4,5-triphosphate accumulation, trigger premature emigration of immature B cells from bone marrow.

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¹ This work was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant DK047121-11. J.C.C. is an Ida and Cecil Green endowed Professor of Cell Biology.

² Address correspondence and reprint requests to Dr. John C. Cambier, Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, Denver CO 80206. E-mail address: cambierj{at}njc.org

³ Abbreviations used in this paper: SDF-1, stromal cell-derived factor-1; HEL, hen egg lysozyme; mIg, membrane Ig; PIP₃, phosphatidylinositol 3,4,5-trisphosphate;