Positive selection‐associated skin‐homing of fetal thymic gamma/delta T cells

Murine skin‐specific intraepithelial γδ T cells (sIELs) are prototypic non‐lymphoid tissue specific “innate lymphocytes”. Nearly all sIELs express identical Vγ3/Vδ1 γδ T cell receptors (TCR) and originate from the fetal thymus. Previously, we found that positive selection of γδ T cells in the fetal thymus is associated with a unique expression profile of chemokine receptors, such as upregulation of potentially important skin‐homing receptor CCR10, suggesting that a unique selection process of the fetal thymic γδ T cells determines their homing properties and peripheral localization. Confirming this, we now generated CCR10 knockout mice and found that development of γδ T cells in the skin, but not in other tissues, were severely impaired in these mice. Furthermore, we found that positively selected fetal thymic γδ T cells developed into sIELs without requirement of further peripheral TCR/ligand interaction, demonstrating that the central selection process of γδ T cells in the fetal thymus is sufficient to direct their migration and expansion in the skin. These findings may serve a paradigm for understanding development of other tissue‐specific “innate lymphocyte”, including γδ, NK, CD8αα, mucosal associated invariant T cells and B1 B cells, a group of important but poorly understood immune cells.