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-DeltaCT) has been used to compete with wild-type CCL21 in the course of binding to CCR7. Combined administration of siRNA S1P1 and CCL21-DeltaCT 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.