Prostaglandin E2 Suppresses Antifungal Immunity by Inhibiting Interferon Regulatory Factor 4 Function and Interleukin-17 Expression in T Cells

SummaryT helper 17 (Th17) cells play an important role in mucosal host defense through production of the signature cytokines IL-17 and IL-22. Prostaglandin E2 (PGE2) has been shown to enhance IL-17 production by mature Th17 cells. However, when present during Th17 cell differentiation, we found that PGE2 inhibited the transcription factor IRF4 and suppressed production of IL-17 but not IL-22. We show that IRF4 was required for IL-17 expression but inhibited IL-22 expression, highlighting the potential for discordant regulation of these two cytokines in Th17 cells. The pathogenic fungus Cryptococcus neoformans produces PGE2, and we found that it uses PGE2- and IRF4-dependent mechanisms to specifically inhibit induction of IL-17 during Th17 cell differentiation. Blockade of host PGE2 during infection led to increased IL-17 production from CD4+ T cells and increased survival of mice. These findings suggest that host- or pathogen-derived PGE2 can act directly on Th17 cells during differentiation to inhibit IL-17-dependent antimicrobial responses.

Graphical AbstractFigure optionsDownload high-quality image (191 K)Download as PowerPoint slideHighlights
► PGE2 acts during Th17 cell differentiation to inhibit IL-17 and augment IL-22 production
► PGE2 inhibits IRF4, which promotes IL-17 but inhibits IL-22 expression
► Fungal or host-derived PGE2 inhibits IL-17 and enhances Cryptococcus lung infection
► PGE2 blockade with indomethacin during Cryptococcus infection improves host survival