Proximal <i>Lck</i> Promoter–Driven <i>Cre</i> Function Is Limited in Neonatal and Ineffective in Adult γδ T Cell Development

Abstract

During T cell development, <i>Lck</i> gene expression is temporally controlled by its proximal and distal promoters. The <i>pLckCre</i> transgenic mouse available from The Jackson Laboratory, in which the proximal promoter of <i>Lck</i> drives <i>Cre</i> expression, is a commonly used <i>Cre</i> driver line to recombine genes flanked by <i>loxP</i> sites in T cells. <i>pLckCre</i> drives recombination early in thymocyte development and is frequently used to delete genes in αβ and γδ T cells. We found that <i>pLckCre</i> failed to efficiently delete floxed genes in γδ T cells in contrast to a complete deletion in conventional as well as unconventional αβ T cells. Mechanistically, γδ T cells inefficiently transcribed the endogenous proximal <i>Lck</i> promoter compared with αβ T cells during adult thymic development. A small population of γδ T cells that had activated <i>pLckCre</i> was detected, many of which were located in nonlymphoid organs as well as precommitted IL-17- or IFN-γ-producing γδ T effector cells. In newborn thymi, both <i>pLckCre</i> and endogenous <i>Lck</i> proximal promoter expression were substantially enhanced, giving rise to an elevated fraction of γδ T cells with recombined floxed genes that were increased in unique γδ T subsets, such as the IL-17-producing γδ T cells. Our data point out striking differences in <i>Lck</i> transcription between perinatal and adult γδ T cell development. Taken together, the data presented in this study shed new light on γδ T cell development and stimulate a reanalysis of data generated using the <i>pLckCre</i> transgenic mice.