Suppression of PI(3,4,5)P3 production is a key determinant of B cell anergy

• Published in: Immunity (Cambridge, Mass.) Vol. 31; no. 5; pp. 749 - 760
• Main Authors: Browne, Cecille D., Del Nagro, Christopher J., Cato, Matthew H., Dengler, Hart S., Rickert, Robert C.
• Format: Journal Article
• Language: English
• Published: 05.11.2009
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2009.08.026

Anergy is a critical physiologic mechanism to censor self-reactive B cells. However, a biochemical understanding of how anergy is achieved and maintained is lacking. Herein, we investigated the role of the phosphoinositide 3-kinase (PI3K) lipid product PI(3,4,5)P 3 in B cell anergy. We found reduced generation of PI(3,4,5)P 3 in anergic B cells, which was attributable to reduced phosphorylation of the PI3K membrane adaptor CD19, as well as increased expression of the inositol phosphatase PTEN. Sustained production of PI(3,4,5)P 3 in B cells, achieved through conditional deletion of Pten, resulted in failed tolerance induction and abundant autoantibody production. In contrast to wildtype immature B cells, BCR engagement of PTEN-deficient immature B cells resulted in activation and proliferation, indicating a central defect in early B cell responsiveness. These findings establish repression of the PI3K signaling pathway as a necessary condition to avert the generation, activation and persistence of self-reactive B cells.