Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy.
Anergy is a critical physiologic mechanism to sensor 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 wild-type immature B cells, B cell receptor 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.
Browne
Cecille D
CD
Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center & Program of Signal Transduction, Cancer Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Del Nagro
Christopher J
CJ
Cato
Matthew H
MH
Dengler
Hart S
HS
Rickert
Robert C
RC
D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction
D018941:Antigens, CD19; D017261:Glycosylphosphatidylinositols; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; C060974:phosphatidylinositol 3,4,5-triphosphate