FOXO1 re-expression with a dual-recombinase allele rescues class switching in germinal center B cells.

Modeling complex (patho)physiological processes by sequential targeted mutagenesis in mice is limited by the lack of precision of cellular targeting and complex breeding strategies. We present a new Cre/DreERT2 dual-recombinase germinal center B cell (GCBC)-specific strain, with co-expression of the recombinases from a single allele. This enables highly efficient Cre-mediated FOXO1 knockout in GCBCs in vivo, followed by time-controlled, efficient Dre-mediated FOXO1 re-expression in the same cells, leading to functional rescue of GC compartmentalization and class switch recombination. The present approach can be easily adapted to other cellular contexts.