IMMUNOBIOLOGY Critical role of class IA PI3K for c-Rel expression in B lymphocytes

The fact that the Xid mutation of Btk impairs the ability of pleckstrin homo-logy domain of Btk to bind phosphatidyl-inositol-(3,4,5)-trisphosphate, a product of class IA phosphoinositide-3 kinases (PI3Ks), has been considered strong evi-dence for the hypothesis that Btk func-tions downstream of PI3Ks. We demon-strate here that the Xid mutation renders the Btk protein unstable. Furthermore, class IA PI3K- and Btk-deficient mice show different phenotypes in B-cell develop-ment, collectively indicating that PI3Ks and Btk differentially function in BCR signal transduction. Nevertheless, both PI3K and Btk are required for the activa-tion of NF-B, a critical transcription fac-tor family for B-cell development and function. We demonstrate that PI3Ks maintain the expression of NF-B pro-teins, whereas Btk is known to be essen-tial for IB degradation and the transloca-tion of NF-B to the nucleus. The loss of PI3K activity results in marked reduction of c-Rel and to a lesser extent RelA expres-sion. The lentivirus-mediated introduc-tion of c-Rel corrects both developmental and proliferative defects in response to BCR stimulation in class IA PI3K-deficient B cells. These results show that the PI3K-mediated control of c-Rel expres-sion is essential for B-cell functions. (Blood. 2009;113:1037-1044