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

2012; Cell Press; Volume: 36; Issue: 4 Linguagem: Inglês

10.1016/j.immuni.2012.02.013

1097-4180

Patricia Valdez, Paul J. Vithayathil, Brian Janelsins, Arthur L. Shaffer, Peter R. Williamson, Sandip K. Datta,

Antifungal resistance and susceptibility

T 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.