Immunology

Analysis of Cytokine Regulators Inducing Interferon- Production by Mouse Uterine Natural Killer Cells

Abstract

In mice and women, terminal differentiation of uterine Natural Killer (uNK) cells commences during endometrial decidualization. Both proliferation and interferon (IFN)- are induced. UNK cell precursors appear to home from secondary lymphoid organs to decidualizing uteri and localize mesometrially to the central decidua basalis, the site of maternal arterial modification at gestation days (gd) 9.5-10. In mice, genetic absence of uNK cells results in absence of pregnancy-induced spiral artery modification. Administration of IFN- to uNK-, pregnant females induces arterial modifications without fetal loss. This study addresses roles of cytokines, known in other tissues to differentiate and activate NK cells, in induction of IFN- production in normal mouse implantation sites. Fecundity, implantation site morphometry and IFN- quantification in IL-12p40^0/0, IL-18^0/0, dual IL-12p40^0/0/IL-18^0/0 and congenic strains revealed importance of both IL-12 and IL-18 in induction of spiral artery modification and IFN- synthesis. Immediately postimplantation, IL-18 was localized transiently to decidual cells but, by gd8, IL-18 was produced solely by uNK cells, suggesting uNK cell precursors are activated by stroma while autocrine signals may maintain uNK cell activation. Using RT-PCR, mesometrial tissue of C57Bl/6J mice was examined in virgin, early postimplantation and midgestation females for expression of the heterodimeric cytokines IL-23 (composed of IL-12p40 and a novel -chain), IL-27 (composed of two IL-12 related chains) and IL-27R. No expression was detected in virgin uteri. The four genes were induced by gd6 and uNK cells isolated from midgestation transcribed IL-23 and IL-27R. This study provides further but still incomplete information regarding uNK cell activation.