Dendritic cells treated with a prostaglandin I2 analog, iloprost, promote antigen-specific regulatory T cell differentiation in mice

Iloprost, a stable prostaglandin I-2 (PGI(2)) analog, can inhibit allergic inflammation in an ovalbumin (OVA)induced asthma model via inhibition of airway dendritic cell (DC) function. However, the underlying mechanism of PGI(2) signaling-mediated immunosuppression remains unclear. This study explored whether iloprost-treated DCs can suppress inflammation by promoting antigen-specific regulatory T cell (Treg) differentiation through PGI(2)-G-protein-coupled receptor (IP). We established an allergic lung inflammation model using a hydrogel biomaterial delivery system and observed that iloprost significantly suppressed OVA-induced Th2 lung inflammation and increased the frequency of OVA-specific Tregs in vivo. We further observed that iloprost-treated DCs displayed tolerogenic characteristics, including low inflammatory cytokine (IL-12, TNF-alpha, IL-6, IL-23) expression levels, high anti-inflammatory cytokine (IL-10) production, and a semimature phenotype. In addition, iloprost-treated DCs increased OVA-specific CD4(+) Foxp3(+) T cell differentiation from naive T cells in an IP-dependent pathway in vitro and in vivo. Blocking experiments showed that iloprost-treated DCs promoted Treg differentiation, at least in part, through programmed death ligand 1 (PD-L1), whereas iloprost-induced PD-Ll expression in DCs was through the IP receptor. Furthermore, iloprost treatment suppressed DC-mediated airway inflammation and increased the frequency of OVA-specific Tregs through PD-Ll in vivo. Taken together, these results show that PGI(2)-IP signaling mediated by iloprost in DCs may lead to immune tolerance, suggesting that the PGI(2) analog has the potential to be applied therapeutically for tolerogenic DC immunotherapy in autoimmune diseases or allergic asthma.