Prostaglandin I2 -orchestrates regulatory and effector T cell–mediated autoimmunity

Abstract

Abstract Tregs maintain tolerance and prevent autoimmune disease by inhibiting T cell activation. There is extensive interest in the application of Tregs in transplantation, autoimmune diseases, and allergy. Our group and others have shown that prostacyclin I2 (PGI2) signaling through the I prostanoid (IP) receptor inhibits allergic airway inflammation. However, it remains unknown whether PGI2 regulates Tregs and Treg-mediated inflammation. We hypothesized that PGI2 skews the immunological balance towards tolerance and away from inflammation. To determine whether PGI2 mediates systemic tolerance, we performed whole animal histopathology on aged WT and IP KO mice. PGI2 protected against autoimmune manifestations including splenomegaly, perivascular-bronchiolar lymphocytic cuffing, and epicarditis that developed in aged IP KO mice. Endogenous PGI2 also promoted Treg Foxp3 expression, suppressive function, and polarization. PGI2 concurrently decreased Teff proliferation and increased Teff susceptibility to Treg-mediated suppression. These studies are the first to show that PGI2 protects against autoimmunity and may represent a novel treatment strategy for Treg-mediated diseases.