Prostaglandin [I.sub.2] signaling licenses Treg suppressive function and prevents pathogenic reprogramming

Introduction Tregs are important components of the adaptive immune system that promote tolerance, prevent the development of autoimmune diseases, and suppress inflammation (1, 2). Tregs are characterized by their expression [...]
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 I2 ([PGI.sub.2]) promoted immune tolerance in models of allergic inflammation; however, the effect of [PGI.sub.2] on Treg function was not investigated. Tregs from mice deficient in the [PGI.sub.2] receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which [PGI.sub.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.sub.2] signaling prevents Treg reprogramming toward a pathogenic phenotype. [PGI.sub.2] analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of [beta]-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that [PGI.sub.2] signaling licenses Treg suppressive function and that [PGI.sub.2] is a therapeutic target for enhancing Treg function.