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The skin as the outmost epithelial tissue is under frequent physical, chemical, and biological assaults. To counter the assaults and maintain the local tissue homeostasis, the skin is stationed with various innate or innate-like lymphocytes such as γδT cells. Increasing evidence suggests that an intrathymically programmed process is involved in coordinated expression of multiple homing molecules on specific γδT cell subsets to direct their localization in different regions of the skin for the protective functions. However, detailed molecular events underlying the programmed skin distribution of specific γδT cell subsets are not fully understood. We report in this study that the temporally and spatially regulated downregulation of chemokine receptor CCR6 on fetal thymic Vγ3(+) epidermal γδT precursors is involved in their thymic egress and proper localization in the epidermis. Failure of downregulation of CCR6 in the mature Vγ3(+) epidermal γδT precursor cells due to the constitutive expression of transgenic CCR6 resulted in their abnormal accumulation in the fetal thymus and reduced numbers of the epidermal γδT cells. In addition, the transgenic expression of CCR6 on the Vγ3(+) γδT cells also improperly increased their distribution in dermis of the skin. Those findings advanced our understanding of the molecular basis regulating the tissue specific distribution of various innate-like γδT cell lymphocytes in the skin.

Programmed Downregulation of CCR6 Is Important for Establishment of Epidermal γδT Cells by Regulating Their Thymic Egress and Epidermal Location