S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and regulatory T cells

Naïve CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. The differentiation of pro-inflammatory T(H)1 and anti-inflammatory Foxp3+ regulatory T cells (Treg) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine-1-phosphate. S1P(1) inhibited extrathymic and natural Treg generation while driving T(H)1 cell development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through mTOR and antagonized TGF-β function mainly by attenuating sustained Smad3 activity. S1P(1) function was dependent upon endogenous sphingosine kinase activity. Remarkably, two seemingly unrelated immunosuppressants FTY720 and rapamycin targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 and Treg cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification.