*3.5. Treg Cells*

Regulatory T cells (Tregs) are critical for immune tolerance in that they suppress inflammation, promote tolerance, and inhibit the development of autoimmune disorders [9,31]. Development of Tregs is promoted by the transcription factor Forkhead box p3 (Foxp3) [31]. Regulatory T cells are crucial for suppressing type 2 inflammation and do so through expressing GATA-binding protein 3 (GATA3) and interferon regulatory factor 4 (IRF4) in order to inhibit Th2 cells [31]. Tregs that express the inhibitory receptor immunoglobulin-like transcript 3 (ILT3) are unable to suppress the Th2 response [31].

In vivo studies reveal that prostacyclin signaling promotes immune tolerance and Treg stability. In the ovalbumin sensitization and challenge model, immune tolerance can be induced by exposing WT mice to aerosolized ovalbumin prior to sensitization. IP KO mice did not develop tolerance in this protocol, suggesting that IP signaling was critical for tolerance induction [32]. Interestingly, in this study, a surprising finding was

that there were more, not fewer, Treg in the lungs of IP KO mice. This result suggested that Treg in IP KO mice may be less functional than those in WT mice [32]. A follow-up study confirmed that IP signaling was critical for Treg effector function. Treg from IP KO mice had decreased Foxp3 expression compared to WT Treg, and Foxp3 expression is correlated with Treg suppressive function [31]. In an in vivo adoptive transfer model, Treg from IP KO mice was significantly less able to suppress allergic inflammation compared to WT Treg [31]. Lung IP KO Tregs isolated from mice had a significantly greater ILT3, revealing that prostacyclin signaling attenuated ILT3 expression on Tregs. Further, in vitro studies showed that cicaprost promoted Foxp3 expression in both mouse and human T cells polarized down the Treg pathway. Another group reported that in the ovalbumin-induced asthma model, iloprost promoted regulatory T cell differentiation from naïve T cells [9]. Thus, prostacyclin signaling is critical for optimal Treg function.
