A team led by Dr. Yu-Wen Su from the Immunology Research Center demonstrated that PP4 is indispensable for preventing DNA replication stress that could interfere with class switch recombination (CSR), thereby promoting antibody switching during the humoral immune response.
PP4 is a serine/threonine phosphatase required for immunoglobulin (Ig) VDJ recombination and pro-B/pre-B cell development in mice, which has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. Dr. Su and her team have previously showed that PP4 is required for mouse B cell development, germinal center (GC) formation and Ig CSR.
The team further investigated the mechanisms underlying this requirement and demonstrated that murine PP4-deficient B lymphocytes have a defect in cell proliferation. In response to LPS + IL-4, stimuli that trigger IgG1 production, these PP4-deficient B cells showed inefficient phosphorylation of ATR, leading to reduced retention of γH2AX-NBS1 complexes at sites of DNA damage, and compromised switching to IgG1. However, beyond the cell proliferation phase, conditional deletion of PP4 under the control of AID/cre completely restored normal IgG1 production in mutant B cell cultures. In those mutant B cells, p53 activity was strongly induced. In vivo, co-deletion of PP4 and p53 by AID/cre partially rescued switching to IgG1 in B cells of mice immunized with TNP-KLH. Our findings establish that PP4 is indispensable for preventing DNA replication stress that could interfere with CSR, thereby promoting antibody switching during the humoral immune response.
Citation: Chen, MY; Hsu, WC; Hsu, SC; Yang, YS; Chuang, TH; Lin, WJ; Tan, TH; Su, YW. PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency. Cell Death and Differentiation. 2018 Sep 20; Article in Press.