PTEN-regulated AID transcription in Germinal center B cells is essential for the class-switch recombination and IgG antibody responses

Abstract

Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM responses. The GCs fail to produce the IgG1 B cells, the high affinity antibodies and nearly lost the dark zone (DZ) in Ptenfl/fl Cγ1Cre/+ mice after immunization, suggesting the impaired GC structure. Further mechanistic investigations show that LPS- and interleukin-4 stimulation induced the transcription of Cγ1 in IgM-BCR expressing B cells, which efficiently disrupts PTEN transcription, results in the hyperphosphorylated AKT and FoxO1 and in turn the suppression of AID transcription. Additionally, the reduced transcription of PTEN and AID is also validated by investigating the IgM-BCR expressing GCBs from Ptenfl/fl Cγ1Cre/+ mice upon immunization. In conclusion, PTEN regulated AID transcription in GCBs is essential for the CSR and IgG antibody responses.