Iloprost-treated dendritic cells promote antigen-specific regulatory T cell differentiation in mice

Abstract

Abstract Iloprost, a stable prostaglandin I2 (PGI2) analog, can inhibit allergic inflammation in an OVA-induced asthma model via inhibition of airway dendritic cell (DC) function. However, the underlying mechanism of PGI2 signaling-mediated immunosuppression remains unclear. This study explored whether iloprost-treated DCs can suppress inflammation by promoting antigen-specific regulatory T cell (Treg) differentiation. 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-12p70, TNF-α, 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 naïve T cells in vitro and in vivo. Blocking experiments showed that iloprost-treated DCs promoted Treg differentiation, at least in part, through PD-L1. Furthermore, iloprost treatment suppressed DC-mediated airway inflammation and increased the frequency of OVA-specific Tregs through PD-L1 in vivo. Taken together, these results show that PGI2 signaling in DCs may lead to immune tolerance, suggesting that the PGI2 analog has the potential to be applied therapeutically for tolerogenic DC immunotherapy in autoimmune diseases or allergic asthma.