Decidual NK cells regulate key developmental processes at the human fetal-maternal interface

Abstract

Human CD56bright NK cells accumulate in the maternal decidua during pregnancy and are found in direct contact with fetal trophoblasts. Several mechanisms have been proposed to explain the inability of NK cells to kill the semiallogeneic fetal cells. However, the actual functions of decidual NK (dNK) cells during pregnancy are mostly unknown. Here we show that dNK cells, but not peripheral blood–derived NK subsets, regulate trophoblast invasion both in vitro and in vivo by production of the interleukin-8 and interferon-inducible protein–10 chemokines. Furthermore, dNK cells are potent secretors of an array of angiogenic factors and induce vascular growth in the decidua. Notably, such functions are regulated by specific interactions between dNK-activating and dNK-inhibitory receptors and their ligands, uniquely expressed at the fetal-maternal interface. The overall results support a 'peaceful' model for reproductive immunology, in which elements of innate immunity have been incorporated in a constructive manner to support reproductive tissue development.

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Figure 1: Enhanced production of growth factors by human dNK cells.
Figure 2: Chemokine expression profile of human invasive extravillous trophoblasts.
Figure 3: dNK cells direct trophoblast migration through production of the chemokines IP-10 and IL-8.
Figure 4: In vitro and in vivo angiogenic properties of dNK cells.
Figure 5: MHC class I–recognizing receptors regulate growth factor production by dNK cells.
Figure 6: Stimulation of natural cytotoxicity receptors on dNK cells promotes production of growth factors.

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Acknowledgements

We would like to thank O. Wald, N. Stern, G. Cohen, G. Katz, T. Gonen-Gross and S. Cohen for assistance. We would like to also thank I. Ariel and A. Peled for discussion. O.M. is supported by research grants from the Israel Cancer Research Foundation, The Israel Science Foundation, European Commission (QLK2-CT-2002-011112) and the Israeli Cancer Research Institute. S.Y. is supported by a grant from the Office of the Chief Scientist, Israel Ministry of Health (5695). J.H. is supported by fellowships from the Foulkes Foundation and Israeli Ministry of Education.

Author information

J.H. conceived the idea for this project, designed all experiments, performed NK cell isolations, gene arrays and all in vitro and in vivo functional experiments. D.G.-W., Y.H., C.G., S.N.-Y. and S.Y. provided human tissue samples, performed trophoblast isolation and chemokine receptor immunohistochemistry. I.A. and E.K. provided technical assistance with angiogenesis assays. T.I.A. and A.P. provided soluble NK receptors. D.B. and V.Y. developed a protocol of affinity histochemistry with NCR-Fc reagents. D.P. confirmed pathology results. L.C.-D., R.G. and I.M. provided technical assistance with in vivo experiments. O.M. supervised the project, provided crucial ideas and helped with data interpretation. J.H. wrote the manuscript with O.M. and S.Y.

Correspondence to Simcha Yagel or Ofer Mandelboim.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Chemokine receptor expression on human invasive trophoblasts. (PDF 57 kb)

Supplementary Fig. 2

Characterization of dNK clones for LIR and KIR expression. (PDF 62 kb)

Supplementary Table 1

Average normalized values obtained from genearray analysis on human dNK cells. (XLS 2779 kb)

Supplementary Table 2

Transcription profile of selected chemokines and angiogenic factors in dNK cells revealed by microarray analysis. (PDF 68 kb)

Supplementary Table 3

Semiquantative RT-PCR analysis of chemokines in human dNK cells. (PDF 79 kb)

Supplementary Table 4

Chemokine receptor transcription on HLA-G+ purified human invasive decidual trophoblasts. (PDF 56 kb)

Supplementary Methods (PDF 197 kb)

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