AID governs plasma cell fate
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 AIDR112H mouse model that is devoid of AID activity. The increased GC response is associated with accumulation of GC B cells predominantly in the light zone in immunized AIDR112H mice. AIDR112H 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 AIDR112H B cells while ectopic expression of catalytic active AID in AIDR112H B cells rescued plasma cell generation. AIDR112H impaired recruitment of AID to the Irf4 promoter/enhancer and disrupted the interaction with the Ten-eleven Translocation 2 (TET2). Consequently, DNA demethylation at the Irf4 promoter/enhancer was hindered, thereby impeding the Irf4 expression in GC B cells. This data reveals a B cell-intrinsic mechanism that governs the plasma cell fate decision through epigenetic remodeling mediated by AID.