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

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Abstract 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. Key messages AID deficiency leads to accumulation of a transitional (t)GC population of B cells with low expression of GL7 and failure to up-regulate IRF4 AID deamination activity is needed to promote up-regulation of IRF4 for plasma cell differentiation. Co-operation between TET2 and AID facilitates demethylation of the Irf4 enhancer/promoter.

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