Decidual CXCR4(+)CD56(bright)NK cells as a novel NK subset in maternal–foetal immune tolerance to alleviate early pregnancy failure

Natural killer (NK) cells preferentially accumulate at maternal–foetal interface and are believed to play vital immune‐modulatory roles during early pregnancy and related immunological dysfunction may result in pregnant failure such as recurrent miscarriage (RM). However, the mechanisms underlying the establishment of maternal–foetal immunotolerance are complex but clarifying the roles of decidual NK (dNK) cells offers the potential to design immunotherapeutic strategies to assist RM patients. In this report, we analysed RNA sequencing on peripheral NK (pNK) and decidual NK cells during early pregnancy; we identified an immunomodulatory dNK subset CXCR4(+)CD56(bright)dNK and investigated its origin and phenotypic and functional characteristics. CXCR4(+)CD56(bright)dNK displayed a less activated and cytotoxic phenotype but an enhanced immunomodulatory potential relative to the CXCR4 negative subset. CXCR4(+)CD56(bright)dNK promote Th2 shift in an IL‐4‐dependent manner and can be recruited from peripheral blood and reprogramed by trophoblasts, as an active participant in the establishment of immune‐tolerance during early pregnancy. Diminished CXCR4(+) dNK cells and their impaired ability to induce Th2 differentiation were found in RM patients and mouse models of spontaneous abortion. Moreover, adoptive transfer of CXCR4(+) dNK cells to NK‐deficient (Nfil3(–/–)) mice showed great therapeutic potential of CXCR4(+) dNK via recovering the Th2/Th1 bias and reducing embryo resorption rates. The identification of this new dNK cell subset may lay the foundation for understanding NK cell mechanisms in early pregnancy and provide potential prognostic factors for the diagnosis and therapy of RM.