Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling.
Class-switch recombination (CSR) is essential for humoral immunity. However, the regulation of CSR is not completely understood. Here we demonstrate that phosphatidylinositol 3-kinase (PI3K) actively suppressed the onset and frequency of CSR in primary B cells. Consistently, mice lacking the lipid phosphatase, PTEN, in B cells exhibited a hyper-IgM condition due to impaired CSR, which could be restored in vitro by specific inhibition of PI3Kdelta. Inhibition of CSR by PI3K was partially dependent on the transcription factor, BLIMP1, linking plasma cell commitment and cessation of CSR. PI3K-dependent activation of the serine-threonine kinase, Akt, suppressed CSR, in part, through the inactivation of the Forkhead Box family (Foxo) of transcription factors. Reduced PI3K signaling enhanced the expression of AID (activation-induced cytidine deaminase) and accelerated CSR. However, ectopic expression of AID could not fully overcome inhibition of CSR by PI3K, suggesting that PI3K regulates both the expression and function of AID.
Omori
Sidne A
SA
Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center and Program of Signal Transduction, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Cato
Matthew H
MH
Anzelon-Mills
Amy
A
Puri
Kamal D
KD
Shapiro-Shelef
Miriam
M
Calame
Kathryn
K
Rickert
Robert C
RC
D000818:Animals; D002454:Cell Differentiation; D003564:Cytidine Deaminase / Q000378:metabolism; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006868:Hydrolysis; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007075:Immunoglobulin M / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010950:Plasma Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D003564:Cytidine Deaminase; D051858:Forkhead Transcription Factors; D007075:Immunoglobulin M; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D014157:Transcription Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C513258:Prdm1 protein, mouse; C487757:Pten protein, mouse