title: Unique Eomes(+) NK Cell Subsets Are Present in Uterus and Decidua During Early Pregnancy.
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 differ from peripheral NK cells. In humans, Eomes(+) decidual NK (dNK) cells express 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 dNK 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 include CD49a(-)CD49b(+) conventional NK cells and CD49a(+) cells. Notably, Eomes(+)CD49a(+) cells are absent in spleen and liver. Decidual and uterine Eomes(+)CD49a(+) cells can be dissected in two peculiar cell subsets according to CD49b expression. CD49a(+)CD49b ((-)) and CD49a(+)CD49b(+) cells are enriched in immature CD11b(low)CD27(high) cells, while CD49a(-)CD49b(+) cells contain higher percentages of mature CD11b(high)CD27(low) 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.
authors.affiliation: G. Gaslini Institute , Genoa , Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Montaldo
authors.affiliation: Department of Experimental Medicine (DIMES), Università degli Studi di Genova , Genoa , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vacca
authors.affiliation: G. Gaslini Institute , Genoa , Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Chiossone
authors.affiliation: Department of Experimental Medicine (DIMES), Università degli Studi di Genova , Genoa , Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Croxatto
authors.affiliation: G. Gaslini Institute , Genoa , Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loiacono
authors.affiliation: IRCCS AOU San Martino-IST , Genoa , Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Martini
authors.affiliation: IRCCS AOU San Martino-IST, Genoa, Italy; Department of Neurosciences Rehabilitation Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Università degli Studi di Genova, Genoa, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie - INSERM, Ecole Normale Supérieure de Lyon, Université Lyon 1 , CNRS, Lyon , France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.affiliation: Department of Immunology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine (DIMES), Università degli Studi di Genova, Genoa, Italy; IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
keywords: Eomes; ILC; ILC1; NK cells; pregnancy; tissue-resident NK cells