Gene dose matters: Considerations for the use of inducible CD4-CreER^T2 mouse lines

A growing body of evidence suggests that Cre recombinase can be toxic to immune cells in various experimental settings. Cre recombinase toxicity is dependent on the level of Cre activity and may also interfere with cell proliferation. Here, we compared two different published tamoxifen-inducible CD4-CreERT2 mouse lines for their suitability to study the dynamics of T-follicular helper cell responses in vivo. Our data underscore that under certain circumstances inducible Cre toxicity (tamoxifen application results in translocation of preformed CreERT2 to the nucleus) interferes with cell survival and, therefore, necessitates careful interpretation of experimental data and the inclusion of appropriate controls. Interestingly, our data indicate that low expression of CreERT2 can still allow for efficient recombination in proliferating lymphocytes without causing excessive cell loss due to Cre toxicity.