175: The role of interferon epsilon in the immune response in the female reproductive tract

Abstract

In the female reproductive tract (FRT), homeostasis needs to be maintained to enable embryo implantation and development in parallel with priming of the immune system, which protects against localised infection. The FRT is at risk from mucosal pathogens including sexually transmitted infections (STIs) and interestingly, women in the certain stages of cycle are more susceptible to STIs. Epithelial cells are the first line of defense against infections in the FRT, where they form a mucosal barrier as well as produce many cytokines and chemokines to provide a mucosal immune response, however, orchestration of this response is still poorly understood. Type I Interferons (IFNs) are important innate cytokines in the immune response against STIs of the mucosal tract. IFN epsilon (e) is a novel type I IFN that was discovered in our laboratory and intriguingly its expression is localised in the FRT, most notably in uterine epithelial cells. Using our gene targeted mice, we have demonstrated that this novel cytokine protects mice from experimental models of STIs – Chlamydia muridarum and Herpes Simplex virus. We are currently assessing the role of IFNe in patient samples. Intriguingly, the responsiveness of the uterus to pathogens is reduced in the presence of progesterone thus providing a window of opportunity for uptake of infection. We demonstrate here, the differential responsiveness of uterine epithelial cells (UEC) to pathogen stimulation, depending on the stage of cycle, which offers a unique insight into the role of the innate immune response in the hormone regulated environment of the FRT. Deletion of IFNe results in a significant reduction in IFN response genes in the FRT, genes that are important in affording a basal level of protection against infections. We also demonstrate that, although constitutively expressed in UEC, levels of IFNe differ with the stages of menstrual cycle stage and indeed at the progestin-regulated and infection sensitive stage of cycle. Indeed, in UEC from women at different stages of cycle and in particular at the window of vulnerability for infections, recombinant IFNe is effective in inducing IFN response genes including MxA and OAS in UEC. Thus, investigation of the role of IFNe in the FRT may identify new therapeutic strategies for manipulating the innate immune response in infection, through regulation of the endogenous control mechanisms.