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

Abstract

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.