Female reproductive tract (FRT) homeostasis is maintained to enable embryo implantation and development in parallel with priming of the immune system to protect against localised infection from mucosal pathogens including sexually transmitted infections (STIs). Type I Interferons (IFNs) are regulators of the host innate immune response to infections. We discovered a novel IFN, IFNε, and demonstrated that it can protect mice against STIs: Chlamydia and Herpes Simplex Virus 2, and that it blocks HIV infection in human T cells. We now demonstrate mechanisms of immune regulation of both non-haematopoietic and haematopoietic cells by IFNε.
Firstly, IFNε is most abundantly expressed in uterine epithelial cells (UECs), unlike other type I IFNs. Our transcriptome studies demonstrate endogenous IFNε affords a basal level of immune defense to UECs, as UECs lacking IFNε have significantly less expression of IFN regulated genes (IRGs, e.g. IRF7). Functionally, IFNε-/- UECs have increased proliferation and increased susceptibility to infection with Chlamydia muridarum in vitro. Furthermore, recombinant IFNε treatment of UEC induces similar IRGs compared to other IFNa/b, demonstrating rIFNε as another potential modulator of FRT-immune cell responses with potential for therapeutic benefit in STIs.
We previously demonstrated that IFNε regulates FRT-haematopoetic cells including NK cells, which are a subset of innate lymphoid cells (ILCs). ILCs are key innate effectors of mucosal immune responses in the lung and the intestine, however there are only limited reports of ILC levels in different parts of the FRT and their function and regulation are largely unknown. We now characterise the composition and regulation of ILCs in the hormone-regulated FRT. Importantly, using our IFNε-/- and IFNAR-/- mice we demonstrate type I IFN regulation of FRT-ILC subsets. These studies may identify new therapeutic strategies for targeting and manipulating FRT-innate immune responses in disease, through regulation of endogenous control mechanisms.