Interferon-epsilon is a novel regulator of NK cell responses in the uterus
Jemma Mayall, Jay C. Horvat, Niamh E. Mangan, Anne Chevalier, Huw McCarthy, D M Hampsey, Chantal Donovan, Alexandra C. Brown, Antony Y. Matthews, Nicole A. de Weerd, Eveline D. de Geus, Malcolm R. Starkey, Richard Kim, Katie Daly, Bridie J. Goggins, Simon Keely, Steven Maltby, Rennay Baldwin, Paul S. Foster, M. J. Boyle, Pradeep S. Tanwar, Nicholas D. Huntington, Paul J. Hertzog, Philip M. Hansbro
Abstract
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.