Essential Role of Sphingosine-1-Phosphate Receptor 1-Bearing CD8+CD44+CCR7+ T Cells in Acute Skin Allograft Rejection

A subset of naturally formed sphingosine‐1‐phosphate receptor 1 (S1P1)‐bearing CD8⁺CD44⁺CCR7⁺ memory T cells has been identified in transplant recipient BALB/c (H‐2^d) mice. The frequency of this subset of memory T cells is significantly increased in the spleen, lymph nodes and skin grafts in the recipient BALB/c mice during acute skin allograft rejections. The immune‐reconstitution with CD8⁺CD44⁺CCR7⁺S1P1⁺ memory T cells facilitates acute skin allograft rejection in SCID mice. Being Th1‐polarized and cytotoxic, CD8⁺CD44⁺CCR7⁺S1P1⁺ memory T cells proliferate and differentiate immediately into effectors upon encountering allo‐antigens. A siRNA against S1P1 inhibits CD8⁺CD44⁺CCR7⁺S1P1⁺ memory T cell‐mediated acute skin allograft rejection in SCID mice by means of knocking‐down S1P1‐expression. CCL21 mutant (CCL21‐ΔCT) has been used to compete with wild‐type CCL21 in the course of binding to CCR7. Combined administration of siRNA S1P1 and CCL21‐ΔCT significantly prolongs the survival of skin allograft in the recipient BALB/c mice by means of inhibiting accumulation of CD8⁺CD44⁺CCR7⁺S1P1⁺ memory T cells in the spleen and the skin grafts. Our data provide direct evidence that S1P1 and CCR7 are involved in the proliferation and trafficking of CD8⁺CD44⁺CCR7⁺S1P1⁺ memory T cells. S1P1 may serve as a functional marker for CD8⁺CD44⁺CCR7⁺ memory T cells. Targeting CD8⁺CD44⁺CCR7⁺S1P1⁺ T cells may be a useful strategy to prolong the survival of allograft transplant.