Tregs require IL-2 signaling for signal transducer and activator of transcription 5–mediated (STAT5-mediated) induction of Foxp3. Although phosphatase 2A (PP2A) is a negative regulator of IL-2 production in effector T cells and Tregs do not produce IL-2, it is not known whether PP2A controls IL-2 signaling in Tregs. To explore the role of PP2A in IL-2 signaling in Tregs, we studied mice engineered to lack PP2A in all Foxp3-expressing cells. We report that PP2A is required to enable Foxp3 expression and to maintain sufficient numbers of Tregs in the thymus. We show for the first time to our knowledge that PP2A prevents the selective loss of surface IL-2Rβ and preserves IL-2R signaling potency in Tregs. The loss of IL-2Rβ in thymus- and spleen-derived Tregs that lack PP2A is because of increased sheddase activity. Pan-sheddase or selective ADAM10 (a disintegrin and metalloproteinase 10) inhibition, like forced expression of IL-2Rβ in PP2A-deficient Tregs, restored IL-2Rβ expression and signaling. Thus, PP2A restrains the sheddase activity of ADAM10 in Tregs to prevent the cleavage of IL-2Rβ from the cell surface to enable competent IL-2R signaling, which is essential for Tregs’ development and homeostasis.
Amir Sharabi, Hao Li, Isaac R. Kasper, Wenliang Pan, Esra Meidan, Maria G. Tsokos, Vaishali R. Moulton, George C. Tsokos
ADAM10 selectively cleaves surface IL-2Rβ in CD4+ Tregs, and PP2A inhibits ADAM10 and restores IL-2 signaling.