p53 represses class switch recombination to IgG2a through its antioxidant function.
Ig class switch recombination (CSR) occurs in activated mature B cells, and causes an exchange of the IgM isotype for IgG, IgE, or IgA isotypes, which increases the effectiveness of the humoral immune response. DNA ds breaks in recombining switch (S) regions, where CSR occurs, are required for recombination. Activation-induced cytidine deaminase initiates DNA ds break formation by deamination of cytosines in S regions. This reaction requires reactive oxygen species (ROS) intermediates, such as hydroxyl radicals. In this study we show that the ROS scavenger N-acetylcysteine inhibits CSR. We also demonstrate that IFN-gamma treatment, which is used to induce IgG2a switching, increases intracellular ROS levels, and activates p53 in switching B cells, and show that p53 inhibits IgG2a class switching through its antioxidant-regulating function. Finally, we show that p53 inhibits DNA breaks and mutations in S regions in B cells undergoing CSR, suggesting that p53 inhibits the activity of activation-induced cytidine deaminase.
Guikema
Jeroen E J
JE
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Schrader
Carol E
CE
Brodsky
Michael H
MH
Linehan
Erin K
EK
Richards
Adam
A
El Falaky
Nahla
N
Li
Daniel H
DH
Sluss
Hayla K
HK
Szomolanyi-Tsuda
Eva
E
Stavnezer
Janet
J
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002469:Cell Separation; D003564:Cytidine Deaminase / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005434:Flow Cytometry; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000276:immunology / Q000378:metabolism*
D000975:Antioxidants; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D003564:Cytidine Deaminase