Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation
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Cytidine Deaminase / metabolism
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Enzyme Activation
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Forkhead Transcription Factors / antagonists & inhibitors
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Forkhead Transcription Factors / metabolism
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Hydrolysis
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Immunoglobulin Class Switching* / genetics
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Immunoglobulin M / metabolism
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Lymphocyte Activation* / genetics
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Mice
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Mice, Mutant Strains
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / physiology
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Plasma Cells / cytology
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Plasma Cells / enzymology*
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Plasma Cells / immunology*
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Proteins c-akt / metabolism
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Recombination, Genetic / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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Transcription Factors / metabolism
Substances
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Forkhead Transcription Factors
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Immunoglobulin M
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Phosphoinositide-3 Kinase Inhibitors
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Prdm1 protein, mouse
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Repressor Proteins
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Transcription Factors
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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Pten protein, mouse
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase