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2016 ; 7
(ä): 489
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Thymocytes in Lyve1-CRE/S1pr1(f/f) Mice Accumulate in the Thymus due to
Cell-Intrinsic Loss of Sphingosine-1-Phosphate Receptor Expression
#MMPMID27877175
Takeda A
; Hossain MS
; Rantakari P
; Simmons S
; Sasaki N
; Salmi M
; Jalkanen S
; Miyasaka M
Front Immunol
2016[]; 7
(ä): 489
PMID27877175
show ga
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.