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Appropriate regulation of IL-17 production in the host can mean the difference between effective control of pathogens and uncontrolled inflammation that causes tissue damage. Investigation of conventional CD4 + T cells (Th17 cells) has yielded invaluable insights into IL-17 function and its regulation. More recently, we and others reported production of IL-17 from innate αβ+ T cell populations, which was shown to occur primarily via IL-23R signaling through the transcription factor STAT-3. In our current study, we identify promyelocytic leukemia zinc finger (PLZF)-expressing iNKT, CD4 - /CD8 + , and CD4 - /CD8 - (DN) αβ+T cells, which produce IL-17 in response to TCR and IL-1 receptor ligation independently of STAT-3 signaling. Notably, this noncanonical pathway of IL-17 production may be important in mucosal defense and is by itself sufficient to control pathogenic Staphylococcus aureus infection at the ocular surface., (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)

Staphylococcus aureus causes most infections of human skin and soft tissue and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin 19 (IL-19), IL-20 and IL-24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We found here that those cytokines promoted cutaneous infection with S. aureus in mice by downregulating IL-1β- and IL-17A-dependent pathways. We noted similar effects of those cytokines in human keratinocytes after exposure to S. aureus, and antibody blockade of the IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for IL-19, IL-20 and IL-24 during infection that could be therapeutically targeted to alter susceptibility to infection.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Staphylococcus aureus causes the majority of human skin and soft tissue infections, and is a major infectious cause of mortality. However, host defense mechanisms against S. aureus are incompletely understood. Interleukin (IL)-19, -20, and -24 signal through STAT3-dependent type I and type II IL-20 receptors and have been associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We hypothesized these cytokines may play a role in S. aureus skin infections. We show here that this family of cytokines promotes cutaneous S. aureus infection in mice by STAT3-dependent mechanisms that down-regulate IL-1 beta- and IL-17A-dependent inflammatory pathways required for control of infection. Inhibition of IL-1 beta by these cytokines was consistent with their demonstrated rapid inactivating sumoylation of C/EBP beta, a transcriptional activator of IL-1 beta. Similar effects of these cytokines were seen in human keratinocytes after S. aureus exposure, and antibody blockade of IL-20 receptor signaling improved infectious outcomes in mice. Our findings identify an immunosuppressive role for these cytokines during infection that may be therapeutically targeted to alter infectious susceptibility. [ABSTRACT FROM AUTHOR]