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The p85α regulatory subunit of phosphatidylinositol 3‐kinase critically modulates class switch DNA recombination
Author(s) -
Xu Zhenming,
Zhang Jinsong,
Ho YinWei,
Ho YinWei,
AlQahtani Ahmed,
Pone Egest,
Zan Hong,
Casali Paolo
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.849.8
Subject(s) - immunoglobulin class switching , somatic hypermutation , breakpoint cluster region , protein subunit , phosphatidylinositol , b cell , pi , dna pkcs , antibody , biology , microbiology and biotechnology , signal transduction , kinase , gene , protein kinase a , genetics , biochemistry
Somatic hypermutation (SHM) and class switch DNA recombination (CSR) are central to the maturation of the antibody response. The PI 3‐K signaling plays an important role in the B cell development, proliferation and survival. PI 3‐K was also suggested to negatively regulate CSR by inhibiting AID expression and/or promoting plasmacytoid differentiation. Here, we directly addressed the role of PI 3‐K in CSR and, thereby, the maturation of the T‐dependent antibody response, using mice that are deficient in p85α, the predominant Class I PI 3‐K regulatory subunit. We found that the p85α‐deficiency did not significantly alter proliferation of in vitro stimulated B cells, but significantly decreased CSR to IgG1 or other isotypes, mainly due to a decreased proportion of switched B cells that had undergone five or more divisions. While B cell receptor (BCR)‐crosslinking increased the overall degree of CSR in p85α −/− B cells, it did not rescue the defective CSR in p85α −/− B cells at high division numbers, suggesting a BCR signaling‐independent function of PI 3‐K in CSR. Accordingly, CSR in p85α −/− mice immunized with a T‐dependent antigen was impaired, leading to a three‐ to five‐fold decrease of antigen‐specific IgG1, as compared to their wildtype counterparts. Thus, p85α and, therefore, PI 3‐K signaling, plays an important role in CSR and an effective antibody response. Supported by NIH grants AI 45011, AI 60573 and AR 40908.