Redundant and unique roles of two enhancer elements in the TCRγ locus in gene regulation and γδ T cell development

Many mammalian genes, including those encoding antigen receptors, contain more than one enhancer element. Deleting one element often does not prevent expression, but functional redundancy has never been directly demonstrated by gene targeting of multiple elements. We demonstrate that simultaneous deletion of two enhancer/LCR-like elements in the TCR Cgamma1 cluster, HsA and 3'E-Cgamma1, severely diminishes TCRgamma transcription, selectively impairs development of gammadelta thymocyte subsets, but only modestly reduces TCRgamma gene rearrangement, while deletion of each element separately has little effect. In contrast to these results in thymocytes, deletion of HsA alone reduces transcription of one Vgamma gene specifically in peripheral gammadelta T cells. Thus, the two elements exhibit functional redundancy in thymocytes but also have unique functions in other settings.