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 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Tregs from mice deficient in the PGI2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which PGI2 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 PGI2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI2 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 PGI2 signaling licenses Treg suppressive function and that PGI2 is a therapeutic target for enhancing Treg function.
Allison E. Norlander, Melissa H. Bloodworth, Shinji Toki, Jian Zhang, Weisong Zhou, Kelli Boyd, Vasiliy V. Polosukhin, Jacqueline-Yvonne Cephus, Zachary J. Ceneviva, Vivek D. Gandhi, Nowrin U. Chowdhury, Louis-Marie Charbonnier, Lisa M. Rogers, Janey Wang, David M. Aronoff, Lisa Bastarache, Dawn C. Newcomb, Talal A. Chatila, R. Stokes Peebles Jr.
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