AID facilitates TET2 demethylation of Irf4 for plasma cell fate in germinal center B cells

Activation-induced cytidine deaminase (AID) is essential for B cell affinity maturation. We investigated why AID deficiency gives rise to giant germinal centers (GC) using the AID ^R112H mouse model that is devoid of AID activity. The increased GC response was associated with accumulation of GC B cells in the light zone in immunized AID ^R112H mice. AID ^R112H GC B cells had reduced capacity to up-regulate IRF4 to initiate plasma cell differentiation, leading to accumulation of a transitional GC population with reduced GL7 expression. Genetic introduction of a high affinity B cell receptor (BCR) was unable to restore plasma cell differentiation of AID ^R112H B cells while ectopic expression of catalytic active AID rescued plasma cell generation. AID ^R112H impaired recruitment of AID to the Irf4 promoter/enhancer and disrupted the interaction with Ten-eleven Translocation 2 (TET2). Consequently, DNA demethylation at the Irf4 promoter/enhancer was reduced in AID ^R112H GC B cells and impeded high Irf4 expression for transition into plasma cells. This data reveals a B cell-intrinsic mechanism that governs the plasma cell fate decision through epigenetic remodeling mediated by AID in cooperation with TET2.