Imbalanced PTEN and PI3K Signaling Impairs Class Switch Recombination.
Class switch recombination (CSR) generates isotype-switched Abs with distinct effector functions. B cells express phosphatase and tensin homolog (PTEN) and multiple isoforms of class IA PI3K catalytic subunits, including p110α and p110δ, whose roles in CSR remain unknown or controversial. In this article, we demonstrate a direct effect of PTEN on CSR signaling by acute deletion of Pten specifically in mature B cells, thereby excluding the developmental impact of Pten deletion. We show that mature B cell-specific PTEN overexpression enhances CSR. More importantly, we establish a critical role for p110α in CSR. Furthermore, we identify a cooperative role for p110α and p110δ in suppressing CSR. Mechanistically, dysregulation of p110α or PTEN inversely affects activation-induced deaminase expression via modulating AKT activity. Thus, our study reveals that a signaling balance between PTEN and PI3K isoforms is essential to maintain normal CSR.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Zhangguo
Z
Chen
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Andrew
A
Getahun
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045.
Xiaomi
X
Chen
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045.
Yonatan
Y
Dollin
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
John C
JC
Cambier
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Jing H
JH
Wang
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007074:Immunoglobulin G; D020033:Protein Isoforms; D007073:Immunoglobulin E; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase