A new report reveals that Foxp3 controls Treg suppressive function through a ceramide signaling pathway. A new report reveals that Foxp3 controls Treg suppressive function through a ceramide signaling pathway. CITATION Apostolidis SA, Rodriguez‐Rodriguez N, Suarez‐Fueyo A, et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nature Immunol 2016; 17: 556–564. Foxp3+ T regulatory cells (Tregs) are a CD4+ T cell lineage critical for the maintenance of peripheral self‐tolerance. Expansion of Treg populations and enhancement of their regulatory function has been an attractive strategy for inhibiting graft‐specific T cell responses and achieving immunological tolerance following transplantation. While the suppressive function of Tregs has been well studied, novel strategies for improving their therapeutic potential are needed. In particular, methods for selectively enhancing Treg function in vivo could lead to improved outcomes following organ transplantation. An increasing body of research has delineated the ways in which CD4+ T cell subsets uniquely utilize extracellular signals (ie, cytokines or cosignaling) for survival and function. In particular, Tregs are known to have several distinct signaling requirements compared with non‐Treg CD4+ T cells, which are frequently described as conventional T cells (Tconv). When compared with Tconv, Tregs require continuous T cell receptor signaling and are particularly dependent on CD28 and interleukin‐2 (IL‐2) signals in the periphery. Paradoxically, Tregs are known to have relatively diminished activity of signaling pathways downstream of these extracellular signals, specifically the mTOR and the PI3K/AKT pathways. Thus, an important and unresolved question remains: How do Tregs tune down these intracellular signaling pathways relative to Tconv? In a recent Nature Immunology paper, Apostolidis and colleagues sought to investigate the mechanisms underlying diminished mTOR activity in Tregs by focusing on the serine–threonine phosphatase PP2A (protein phosphatase 2A). They found greater activity of PP2A in Tregs compared with Tconv and, strikingly, Treg‐specific genetic deletion of PP2A in mice resulted in profound multiorgan autoimmune disease. This phenotype included the loss of peripheral T cell homeostasis and extensive lymphoproliferation in secondary lymphoid organs, the severity of which is reminiscent of the Foxp3 null scurfy phenotype. These findings clearly demonstrate a central role for PP2A in Treg function. In investigating the mechanisms underlying increased PP2A activity in Tregs, the authors discovered that Tregs displayed hypophosphorylation at the PP2A‐inhibitory Tyr307 residue, which inactivates PP2A function. Phosphorylation of this residue is known to be controlled by the SET–ceramide pathway (Figure 1). Intriguingly, Tregs contained significantly greater concentrations of several ceramide species compared with Tconv, suggesting that maintenance of higher Treg ceramide levels are responsible for the relative hypophosphorylation and increased activity of PP2A in Tregs. How exactly do Tregs end up with increased intracellular ceramides relative to Tconv? The answer lies in the expression of sphingomyelin synthase 1 (SMS1), an enzyme involved in ceramide catabolism that is known to have relatively low expression in Tregs. Apostolidis and colleagues showed that the SGMS1 gene is a direct target of Foxp3, thus delineating a cell‐intrinsic mechanism by which Tregs maintain PP2A activity: Foxp3 expression inhibits SGMS1 expression, resulting in the maintenance of elevated intracellular ceramide concentrations and diminished inhibitory PP2A Tyr307 phosphorylation. The characterization of Treg‐specific ceramide regulation offers several potential translations to transplantation. Because manipulation of the ceramide–PP2A axis does not affect the expression of known Treg suppressive receptors (i.e. CTLA‐4, PD‐1 and GITR), the ceramide–PP2A axis represents an additional layer of Treg biology that could be manipulated to metabolically stabilize Treg function. Several novel therapeutic strategies for transplantation could be envisioned from this elegant work. For example, during the in vitro propagation of Tregs, such as for the use of adoptive transfer approaches to preventing graft rejection, use of sphingomyelinase might enhance Treg potency. Additionally, perhaps therapeutic silencing of SGMS1 or direct augmentation of PP2A via blockade of the Tyr307 phosphorylation site could improve Treg function in vivo. Overall, this elegant study offers further evidence that Tregs have distinct signaling requirements compared with Tconv, and provides additional strength to the concept that Tregs can be successfully manipulated to prevent graft rejection. Drs. Krummey and Ford are with the Emory Transplant Center at Emory University School of Medicine in Atlanta. Dr. Ford is also section editor for “Literature Watch.”