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Inositol 1,4,5-Trisphosphate 3-Kinase B Is a Negative Regulator of BCR Signaling That Controls B Cell Selection and Tolerance Induction

The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121

Inositol 1,4,5-trisphosphate 3-kinase B (or Itpkb) converts inositol 1,4,5-trisphosphate to inositol 1,3,4,5-tetrakisphosphate upon Ag receptor activation and controls the fate and function of lymphocytes. To determine the role of Itpkb in B cell tolerance, Itpkb^–/– mice were crossed to transgenic mice that express a BCR specific for hen egg lysozyme (IgHEL). B cells from Itpkb^–/– IgHEL mice possess an anergic phenotype, hypoproliferate in response to cognate Ag, and yet they exhibit enhanced Ag-induced calcium signaling. In IgHEL transgenic mice that also express soluble HEL, lack of Itpkb converts anergy induction to deletion. These data establish Itpkb as a negative regulator of BCR signaling that controls the fate of developing B cells and tolerance induction.

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¹ Address correspondence and reprint requests to Dr. Michael P. Cooke, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121. E-mail address: mcooke{at}gnf.org

² Abbreviations used in this paper: [Ca²⁺]_i, intracellular Ca²⁺ concentration; ER, endoplasmic reticulum; HEL, hen egg lysozyme; IP3, inositol 1,4,5-trisphosphate; IP4, inositol 1,3,4,5-tetrakisphosphate; Itpkb, inositol 1,4,5-trisphosphate 3-kinase B; mHEL, membrane-bound hen egg lysozyme; PLC, phospholipase C; sHEL, soluble hen egg lysozyme; SOC, store-operated calcium; tg, transgenic; WT, wild type.