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

• Published in: The Journal of immunology (1950) 2009-04, Vol.182 (8), p.4696-4704
• Main Authors: Miller, Andrew T, Beisner, Daniel R, Liu, Daorong, Cooke, Michael P
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; Bcl-2-Like Protein 11; Bone Marrow - immunology; Calcium - metabolism; Cell Differentiation - immunology; Cells, Cultured; Gene Deletion; Immune Tolerance - immunology; Inositol Phosphates - pharmacology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - metabolism; Receptors, Antigen, B-Cell - immunology; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0802850

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.