CD34⁺hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells

Abstract

Natural killer (NK) cells are the main lymphoid population in the maternal decidua during the first trimester of pregnancy. Decidual NK (dNK) cells display a unique functional profile and play a key role in promoting tissue remodeling, neoangiogenesis, and immune modulation. However, little information exists on their origin and development. Here we discovered CD34(+) hematopoietic precursors in human decidua (dCD34(+)). We show that dCD34(+) cells differ from cord blood- or peripheral blood-derived CD34(+) precursors. The expression of IL-15/IL-2 receptor common β-chain (CD122), IL-7 receptor α-chain (CD127), and mRNA for E4BP4 and ID2 transcription factors suggested that dCD34(+) cells are committed to the NK cell lineage. Moreover, they could undergo in vitro differentiation into functional (i.e., IL-8- and IL-22-producing) CD56(bright)CD16(-)KIR(+/-) NK cells in the presence of growth factors or even upon coculture with decidual stromal cells. Their NK cell commitment was further supported by the failure to undergo myeloid differentiation in the presence of GM-CSF. Our findings strongly suggest that decidual NK cells may directly derive from CD34(+) cell precursors present in the decidua upon specific cellular interactions with components of the decidual microenvironment.

Liaison between natural killer cells and dendritic cells in human gestation

“…38 Other groups have suggested that dNK cells originate from decidual hematopoietic CD34 1 precursors, demonstrating in vitro that CD34 1 decidual cells cocultured with decidual stromal cells can differentiate into functional CD56 bright CD16 2 NK cells. 39 Differentiation of CD34 1 cells into CD56 bright NK cells has also been demonstrated in other tissues, such as the lymph nodes. 40 Recently, studies in mice have described two waves of distinct hematopoietic cells in the fetal thymus with potential to develop into NK cells.…”

Physiological and Pathological Aspects of Human NK Cells

“…Indeed NK-committed precursors were found in gut, endometrium and placenta (Chinen at al., 2007;Male et al, 2010;Vacca et al, 2011). In all these districts there is a high concentration of CD56 bright NK cells characterized by immune-regulatory activity.…”

“…It has been shown that IL-15 activates E4PB4 that, in turn, would activate Id2 transcription, leading to a definitive NK cell commitment and expansion of NK cell precursors. In humans, E4BP4 and Id2 expression can be observed either in ex-vivoisolated early committed CD34 +/-CD122 + CD127 + NK cell precursors either in in vitro-derived CD117 +/-CD161 + CD56 + LFA-1 -NKG2A -iNK cells Vacca at al., 2011). On the other hand, TOX would influence the activation of T-bet, a TF that correlates with the acquisition of cytolytic activity and the ability to produce IFN- by more differentiated CD161 + CD56 + LFA-1 + NKp46 + CD94/NKG2A + NK cells (Yun et al, 2011).…”

“…For long time dNK cells were supposed to derive from PB NK cells undergone phenotypic and functional modifications upon interaction with decidual microenvironment. Recently, different experimental evidences suggested that dNK cells could derive from NK precursors already present in endometrium or in decidua, able to promptly differentiate upon stimuli given by the onset of pregnancy (Male et al, 2010;Vacca et al, 2011 (Romagnani et al, 2007;Juelke et al, 2010).…”

“…In vitro assays revealed that high dose soluble IL-15 binds to its receptors and promote NK cell differentiation but, in vivo, IL-15 is primarily detectable complexed to its IL-15 Receptor (IL15-R) present on accessory (stromal) cells (Dubois et al, 2002). IL-15/IL15-R complex would then present the cytokine in trans to CD122 + CD132 + cells, meaning that also stromal cells could exert an important role in the terminal differentiation of iNK cells (Miller et al, 1994;Briard et al, 2002;Vacca et al, 2011). Finally, IL-21 have been shown to increase the proportions of CD56 + KIR + cells undergoing in vitro differentiation (Sivori et al, 2003).…”