Abstract

Antigen receptor variable-(diversity)-joining (V(D)J) recombination at the locus encoding the T cell antigen receptor-β (Tcrb) is ordered, with Dβ-to-Jβ assembly preceding Vβ-to-DJβ joining. The molecular mechanism underlying this 'preferred' order of rearrangement remains unclear. Here we show that the Dβ 23–base pair recombination signal sequence (Dβ 23-RSS) contains a specific AP-1 transcription factor–binding site bound by AP-1 and its component c-Fos expressed at a specific stage. Cell-based recombination assays suggested that c-Fos interacted directly with the RAG recombinase and enhanced its deposition to Dβ 23-RSSs, thus conferring the priority of DJβ recombination. Loss of c-Fos decreased Tcrb recombination efficiency and disrupted recombination ordering in vivo. Our results show an unexpected function for c-Fos as a direct regulator of Tcrb recombination, rather than its usual function as a transcription regulator, and provide new insight into the mechanisms of recombination ordering.