Positive selection of dendritic epidermal γδ T cell precursors in the fetal thymus determines expression of skin-homing receptors

The role of cellular selection in the development of γδ T cells remains unclear. Knockout mice lacking a subset of Vγ genes, including Vγ3, contain abundant γδ T cells but are devoid of dendritic epidermal γδT cells (DETCs), which normally express an invariant Vγ3/Vδ1 γδ TCR. A rearranged Vγ2 transgene restored DETC development, but the restored DETCs selectively expressed a unique Vδ gene other than Vδ1, indicating that DETC development involves TCR-based selection. In both normal and transgenic/knockout mice, specific DETC precursors in the fetal thymus were activated and expressed the IL-15 receptor β chain, skin-homing receptors, and thymic exiting receptors. In vitro activation of irrelevant precursors also led to upregulation of the skin-homing receptor, providing an explanation for how thymic selection is coordinated with development of epidermal γδ T cells.