The uterus is a unique mucosal site where immune responses are balanced to be permissive of a fetus, yet protective against infections. Regulation of natural killer (NK) cell responses in the uterus during infection is critical, yet no studies have identified uterine-specific factors that control NK cell responses in this immune-privileged site. We show that the constitutive expression of IFNε in the uterus plays a crucial role in promoting the accumulation, activation, and IFNγ production of NK cells in uterine tissue during Chlamydia infection. Uterine epithelial IFNε primes NK cell responses indirectly by increasing IL-15 production by local immune cells and directly by promoting the accumulation of a pre-pro-like NK cell progenitor population and activation of NK cells in the uterus. These findings demonstrate the unique features of this uterine-specific type I IFN and the mechanisms that underpin its major role in orchestrating innate immune cell protection against uterine infection.
Synopsis: IFNε promotes the accumulation, activation and IFNγ production of NK cells in the uterus through both IL-15-dependent and -independent mechanisms. IFNε-mediated NK cell responses protect against Chlamydia FRT infections.IFNε is produced exclusively by reproductive tract epithelial cells and acts in the uterus to increase IL-15 production by myeloid cells.IFNε and IL-15 production in the uterus increases NK cell haematopoiesis in the bone marrow, increasing NK cell numbers systemically, and NK cell accumulation in the uterus.IFNε acts directly on pre-pro NK cell progenitors in the uterus, promoting their accumulation. IL-15 has no effect on this population.Local production of IFNε in the uterus is required for optimal NK cell activation during infection and IFNε directly increases NK cell CD69 expression ex vivo.IL-15 production downstream of IFNε is responsible for promoting NK cell IFNγ production and cytolytic activity. IFNε and IL-15 co-stimulate and are required in concert for full NK cell function.
IFNε promotes the accumulation, activation and IFNγ production of NK cells in the uterus through both IL-15-dependent and -independent mechanisms. IFNε-mediated NK cell responses protect against Chlamydia FRT infections.