The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR

Regulatory T cells (T-reg cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P(1)) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T-reg cells. Combining loss-and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T-reg precursors and function of mature T-reg cells and affected T-reg cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T-reg cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T-reg cell-mediated immune suppression, the lipid-activated S1P(1)-Akt-mTOR pathway orchestrates adaptive immune responses.