Regulatory T cells (Treg cells) are necessary for maintaining peripheral tolerance. Chi and colleagues show that the receptor S1P1 negatively regulates thymic Treg cell production and blocks Treg cell activity via an Akt-mTor pathway. Regulatory T cells (Treg 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 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of Treg cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic Treg precursors and function of mature Treg cells and affected Treg cell–mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of Treg cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing Treg cell–mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.

TGF-β signaling can promote the induction of regulatory T cells. Chi and colleagues show that the sphingosine 1-phosphate receptor S1P1 inhibits prolonged activity of the signal transducer Smad3 to block the generation of induced regulatory T cells, promoting TH1 differentiation instead. Naive CD4+ T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (TH1) cells and anti-inflammatory Foxp3+ regulatory T cells (Treg cells) was reciprocally regulated by S1P1, a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P1 inhibited the generation of extrathymic and natural Treg cells while driving TH1 development in a reciprocal manner and disrupted immune homeostasis. S1P1 signaled through the kinase mTOR and antagonized the function of transforming growth factor-β mainly by attenuating sustained activity of the signal transducer Smad3. S1P1 function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P1 and mTOR pathway to regulate the dichotomy between TH1 cells and Treg cells. Our studies establish an S1P1-mTOR axis that controls T cell lineage specification.

Significance: Macrophages maintain homeostatic proliferation in the presence of mitogens whereas encounters with invading microorganisms inhibit proliferation and engage a rapid proinflammatory response. Such cell fate change requires an extensive reprogramming of metabolism, and the regulatory mechanisms behind this change remain unknown. We found that myelocytomatosis viral oncogen (Myc) plays a major role in regulating proliferation-associated metabolic programs. However, proinflammatory stimuli suppress Myc and cell proliferation and engage a hypoxia-inducible factor alpha (HIF1α)-dependent transcriptional program that is responsible for heightened glycolysis. Our work indicates that a switch from a Myc-dependent to a HIF1α-dependent transcriptional program may regulate the robust bioenergetic support for inflammatory response, while sparing Myc-dependent proliferation.