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T cell emigration from the thymus is essential for immunological homeostasis. While stromal cell-produced sphingosine-1-phosphate (S1P) has been shown to promote thymocyte egress  via  the S1P receptor, S1PR1, the significance of S1P/S1PR1 signaling in the thymic stromal cells that surround T cells remains unclear. To address this issue, we developed conditional knockout mice ( Lyve1-CRE/S1pr1  f/f  mice) in which  S1pr1  was selectively targeted in cells expressing the lymphatic endothelial cell marker, Lyve1. In these mice, T cells were significantly reduced in secondary lymphoid tissues, and CD62L +  mature CD4 and CD8 single-positive (SP) T cells accumulated in the medulla failed to undergo thymus egress. Using a  Lyve1  reporter strain in which Lyve1 lineage cells expressed tdTomato fluorescent protein, we unexpectedly found that a considerable proportion of the thymocytes were fluorescently labeled, indicating that they belonged to the Lyve1 lineage. The CD4 and CD8 SP thymocytes in  Lyve1-CRE/S1pr1  f/f  mice exhibited an egress-competent phenotype (HSA low , CD62L high , and Qa-2 high ), but were CD69 high  and lacked S1PR1 expression. In addition, CD4 SP thymocytes from these mice were unable to migrate to the periphery after their intrathymic injection into wild-type (WT) mice. In contrast, WT T cells could migrate to the periphery in both WT and  Lyve1-CRE/S1pr1  f/f  thymuses. These results demonstrated that thymocyte egress is mediated by T cell-expressed, but not stromal cell-expressed, S1PR1 and caution against using the  Lyve1-CRE  system for selectively gene deletion in lymphatic endothelial cells.

Thymocytes in Lyve1-CRE/S1pr1f/f Mice Accumulate in the Thymus due to Cell-Intrinsic Loss of Sphingosine-1-Phosphate Receptor Expression