Tregs restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a Th2 response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Tregs. We previously reported that prostaglandin I 2 (PGI 2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI 2 on Treg function was not investigated. Tregs from mice deficient in the PGI 2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which PGI 2 signaling was intact. IP KO Tregs had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared with WT Tregs, which may contribute to the impairment of the IP KO Treg’s ability to suppress Th2 responses. Using fate-mapping mice, we reported that PGI 2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI 2 analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of β-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that PGI 2 signaling licenses Treg suppressive function and that PGI 2 is a therapeutic target for enhancing Treg function.