The transcription complex p52–ETS1 is essential for germinal center formation

The NF-κB family comprises five transcription factors (RELA, RELB, C-REL, NF-κB1 (p50) and NF-κB2 (p52)) that form homo- or heterodimers among themselves to regulate gene expression by binding DNA. Here we show that p52 activates transcription without directly binding DNA but as a heterotetrameric complex with ETS1, a transcription factor outside the NF-κB family. By generating a knock-in mouse model (Nfkb2^ki/ki) with three mutated residues on p52 required for its interaction with ETS1, but not RELB, we demonstrate that the p52–ETS1 complex regulates the expression of transcription factors OCT1 and OBF1, which are known to be critical for the germinal center program. Consequently, B cell-intrinsic expression of the p52–ETS1 complex was indispensable for splenic germinal center B cell formation and T cell-dependent antibody responses. Functionally, loss of p52–ETS1 interaction led to diminished antigen-specific IgE, thereby protecting mice from allergic responses. Collectively, our findings expand current knowledge of NF-κB signaling and may provide new therapeutic targets for the treatment of allergic diseases.