IL-10+CTLA-4+ Th2 Inhibitory Cells Form in a Foxp3-Independent, IL-2–Dependent Manner from Th2 Effectors during Chronic Inflammation

Activated Th cells influence other T cells via positive feedback circuits that expand and polarize particular types of response, but little is known about how they may also initiate negative feedback against immunopathological reactions. In this study, we demonstrate the emergence, during chronic inflammation, of GATA-3(+) Th2 inhibitory (Th2i) cells that express high levels of inhibitory proteins including IL-10, CTLA-4, and granzyme B, but do so independently of Foxp3. Whereas other Th2 effectors promote proliferation and IL-4 production by naive T cells, Th2i cells suppress proliferation and IL-4 production. We show that Th2i cells develop directly from Th2 effectors, in a manner that can be promoted by effector cytokines including IL-2, IL-10, and IL-21 ex vivo and that requires T cell activation through CD28, Card11, and IL-2 in vivo. Formation of Th2i cells may act as an inbuilt activation-induced feedback inhibition mechanism against excessive or chronic Th2 responses.