Inactivation of nuclear GSK3β by Ser389 phosphorylation promotes lymphocyte fitness during DNA double-strand break response

Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclear whether this response is associated with distinct survival signals that protect T and B cells. Glycogen synthase kinase 3 beta (GSK3 beta) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3 beta on Ser(389) by p38 MAPK (mitogen-activated protein kinase) is induced selectively by DSBs through ATM (ataxia telangiectasia mutated) as a unique mechanism to attenuate the activity of nuclear GSK3 beta and promote survival of cells undergoing DSBs. Inability to inactivate GSK3 beta through Ser(389) phosphorylation in Ser(389)Ala knockin mice causes a decrease in the fitness of cells undergoing V(D)J recombination and CSR. Preselection-Tcrb repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3 beta knockin mice. Thus, GSK3 beta emerges as an important modulator of the adaptive immune response.