Montaldo Elisa, Vacca Paola, Chiossone Laura, Croxatto Daniele, Loiacono Fabrizio, Martini Stefania, Ferrero Simone, Walzer Thierry, Moretta Lorenzo, Mingari Maria Cristina
G. Gaslini Institute , Genoa , Italy.
Department of Experimental Medicine (DIMES), Università degli Studi di Genova , Genoa , Italy.
Front Immunol. 2016 Jan 7;6:646. doi: 10.3389/fimmu.2015.00646. eCollection 2015.
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.
在人类和小鼠中，蜕膜和子宫自然杀伤（NK）细胞已被证明对成功妊娠有贡献。NK细胞代表“细胞毒性”的1型固有淋巴细胞（ILC），与最近描述的“辅助性”ILC1不同。在这里，我们表明，在人类和小鼠中，子宫内膜/子宫和蜕膜中的大多数1型ILC都表达Eomesodermin（Eomes），因此表明它们在发育上与传统NK细胞相关。然而，它们与外周NK细胞不同。在人类中，Eomes(+)蜕膜NK（dNK）细胞表达CD49a和其他组织驻留标志物，包括CD103、整合素β7、CD9和CD69。CD103的表达有助于识别产生IFNγ的Eomes(+)NK细胞的不同亚群。我们表明，TGFβ可以维持/诱导dNK细胞和蜕膜CD34衍生的NK细胞中CD103和CD9的表达，表明蜕膜微环境可以指导Eomes(+)NK细胞的表型。在小鼠蜕膜和子宫中，Eomes(+)细胞包括CD49a(-)CD49b(+)传统NK细胞和CD49a(+)细胞。值得注意的是，脾脏和肝脏中不存在Eomes(+)CD49a(+)细胞。根据CD49b的表达，蜕膜和子宫中的Eomes(+)CD49a(+)细胞可以分为两个特殊的细胞亚群。在子宫和蜕膜中，CD49a(+)CD49b ((-))和CD49a(+)CD49b(+)细胞富含未成熟的CD11b(low)CD27(high)细胞，而CD49a(-)CD49b(+)细胞含有更高百分比的成熟CD11b(high)CD27(low)细胞。此外，Eomes(+)CD49a(+)CD49b(-)细胞在妊娠期间减少，因此表明这个特殊的亚群可能在妊娠早期而非后期是必需的。相反，蜕膜和子宫中存在的少量Eomes(-)CD49a(+) ILC1群体在妊娠期间增加。CD49b(-)Eomes(±)细胞主要产生TNF，而CD49a(-)CD49b(+)传统NK细胞和CD49a(+)CD49b(+)细胞同时产生IFNγ和TNF。因此，人类和小鼠的蜕膜包含独特的1型ILC亚群，包括Eomes(+)和Eomes(-)细胞，具有特殊的表型和功能特征。我们的研究有助于重新审视人类和小鼠子宫和蜕膜ILC亚群的复杂性，并强调蜕膜微环境在塑造这些细胞特征中的作用。
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