Here we use mice lacking calcineurin B (encoded by Cnb1) or IL-2 (encoded by Il2) in CD11chighMHCII+ cells, and show that calcineurin–NFAT–IL-2 signaling in intestinal CD11chighMHCII+ APCs prevents spontaneous chronic intestinal inflammation in acute and chronic models of induced colitis. Here, PPP3R1 is linked to inflammatory response.