AUTHOR=Montaldo Elisa , Vacca Paola , Chiossone Laura , Croxatto Daniele , Loiacono Fabrizio , Martini Stefania , Ferrero Simone , Walzer Thierry , Moretta Lorenzo , Mingari Maria Cristina 

TITLE=Unique Eomes+ NK Cell Subsets Are Present in Uterus and Decidua During Early Pregnancy

JOURNAL=Frontiers in Immunology

VOLUME=Volume 6 - 2015

YEAR=2016

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2015.00646

DOI=10.3389/fimmu.2015.00646

ISSN=1664-3224

ABSTRACT=Decidual and uterine Natural Killer (NK) cells have been shown to contribute to the successful pregnancy both in humans and mice. NK cells represent “cytotoxic” group 1 innate lymphoid cells (ILCs) and are distinct from the recently described “helper” ILC1. Here we show that both in humans and mice the majority of group 1 ILC in endometrium/uterus and decidua express Eomesodermin (Eomes), thus suggesting that they are developmentally related to conventional NK cells. However, they differed from peripheral NK cells. In humans Eomes+ decidual NK cells expressed CD49a and other markers of tissue residency including CD103, integrin β7, CD9, and CD69. The expression of CD103 allows the identification of different subsets of IFNγ-producing Eomes+ NK cells. We show that TGFβ can sustain/induce CD103 and CD9 expression in decidual NK cells and decidual CD34-derived NK cells, indicating that the decidual microenvironment can instruct the phenotype of Eomes+ NK cells.
In murine decidua and uterus, Eomes+ cells included CD49a-CD49b+ conventional NK cells and CD49a+ cells. Notably, Eomes+CD49a+cells were absent in spleen and liver. Decidual and uterine Eomes+CD49a+ cells could be dissected in two peculiar cell subsets according to CD49b expression. CD49a-CD49b+ cells are enriched in mature CD11bhighCD27low cells, while CD49a+CD49b- and CD49a+CD49b+ cells contain higher percentages of immature CD11blowCD27high cells, both in uterus and decidua. Moreover, Eomes+CD49a+CD49b- cells decrease during gestation, thus suggesting that this peculiar subset may be required in early pregnancy rather than on later phases. Conversely, a minor Eomes-CD49a+ ILC1 population present in decidua and uterus increases during pregnancy. CD49b-Eomes+/- cells produce mainly TNF, while CD49a-CD49b+ conventional NK cells and CD49a+CD49b+ cells produce both IFNγ and TNF. Thus, human and murine decidua contains unique subsets of group 1 ILCs, including Eomes+ and Eomes- cells, with peculiar phenotypic and functional features. 
Our study contributes to re-examination of the complexity of uterine and decidual ILC subsets in humans and mice and highlights the role of the decidual microenvironment in shaping the features of these cells.