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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Accession codes




  1. 1

    Red-Horse, K. et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J. Clin. Invest. 114, 744–754 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Zhou, Y. et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J. Clin. Invest. 99, 2139–2151 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Zhou, Y., Genbacev, O., Damsky, C.H. & Fisher, S.J. Oxygen regulates human cytotrophoblast differentiation and invasion: implications for endovascular invasion in normal pregnancy and in pre-eclampsia. J. Reprod. Immunol. 39, 197–213 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Fisher, S.J. The placental problem: linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia. Reprod. Biol. Endocrinol. 2, 53 (2004).

    Article  Google Scholar 

  5. 5

    Hanna, J. et al. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16– human natural killer cells. Blood 102, 1569–1577 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Drake, P.M. et al. Human placental cytotrophoblasts attract monocytes and CD56(bright) natural killer cells via the actions of monocyte inflammatory protein 1alpha. J. Exp. Med. 193, 1199–1212 (2001).

    CAS  Article  Google Scholar 

  7. 7

    King, A. et al. Functions of human decidual NK cells. Am. J. Reprod. Immunol. 35, 258–260 (1996).

    CAS  Article  Google Scholar 

  8. 8

    Koopman, L.A. et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J. Exp. Med. 198, 1201–1212 (2003).

    CAS  Article  Google Scholar 

  9. 9

    Cooper, M.A., Fehniger, T.A. & Caligiuri, M.A. The biology of human natural killer-cell subsets. Trends Immunol. 22, 633–640 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Hanna, J. et al. Novel insights on human NK cells' immunological modalities revealed by gene expression profiling. J. Immunol. 173, 6547–6563 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Bulmer, J.N. & Lash, G.E. Human uterine natural killer cells: a reappraisal. Mol. Immunol. 42, 511–521 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Tabiasco, J. et al. Human decidual NK cells: unique phenotype and functional properties – a review. Placenta 27 (Suppl. 1), 34–39 (2006).

    Article  Google Scholar 

  13. 13

    Hanna, J. et al. Novel APC-like properties of human NK cells directly regulate T cell activation. J. Clin. Invest. 114, 1612–1623 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Leonard, S. et al. Mechanisms regulating immune cell contributions to spiral artery modification – facts and hypotheses – a review. Placenta 27 (Suppl. 1), 40–46 (2006).

    Article  Google Scholar 

  15. 15

    Monk, J.M., Leonard, S., McBey, B.A. & Croy, B.A. Induction of murine spiral artery modification by recombinant human interferon-gamma. Placenta 26, 835–838 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Ashkar, A.A. & Croy, B.A. Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy. Semin. Immunol. 13, 235–241 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Ashkar, A.A., Di Santo, J.P. & Croy, B.A. Interferon γ contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J. Exp. Med. 192, 259–270 (2000).

    CAS  Article  Google Scholar 

  18. 18

    Guimond, M.J. et al. Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice. Biol. Reprod. 56, 169–179 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Moffett, A. & Loke, Y.W. The immunological paradox of pregnancy: a reappraisal. Placenta 25, 1–8 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Hiby, S.E. et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J. Exp. Med. 200, 957–965 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Langer, N., Beach, D. & Lindenbaum, E.S. Novel hyperactive mitogen to endothelial cells: human decidual NKG5. Am. J. Reprod. Immunol. 42, 263–272 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Tjwa, M., Luttun, A., Autiero, M. & Carmeliet, P. VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res. 314, 5–14 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Goldman-Wohl, D.S., Ariel, I., Greenfield, C., Hanoch, J. & Yagel, S. HLA-G expression in extravillous trophoblasts is an intrinsic property of cell differentiation: a lesson learned from ectopic pregnancies. Mol. Hum. Reprod. 6, 535–540 (2000).

    CAS  Article  Google Scholar 

  24. 24

    McMaster, M.T. et al. Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. J. Immunol. 154, 3771–3778 (1995).

    CAS  PubMed  Google Scholar 

  25. 25

    Corthay, A. et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity 22, 371–383 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Zhang, L. et al. Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res. 60, 3655–3661 (2000).

    CAS  PubMed  Google Scholar 

  27. 27

    Katz, G. et al. MHC class I-independent recognition of NK-activating receptor KIR2DS4. J. Immunol. 173, 1819–1825 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Katz, G., Markel, G., Mizrahi, S., Arnon, T.I. & Mandelboim, O. Recognition of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cell Ig-like receptor two-domain short tail number 4. J. Immunol. 166, 7260–7267 (2001).

    CAS  Article  Google Scholar 

  29. 29

    Gonen-Gross, T. et al. Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J. Immunol. 171, 1343–1351 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Shiroishi, M. et al. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc. Natl. Acad. Sci. USA 100, 8856–8861 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Moretta, A., Bottino, C., Mingari, M.C., Biassoni, R. & Moretta, L. What is a natural killer cell? Nat. Immunol. 3, 6–8 (2002).

    CAS  Article  Google Scholar 

  32. 32

    Lanier, L.L. NKG2D in innate and adaptive immunity. Adv. Exp. Med. Biol. 560, 51–56 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Arnon, T.I. et al. Recognition of viral hemagglutinins by NKp44 but not by NKp30. Eur. J. Immunol. 31, 2680–2689 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Mandelboim, O. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Arnon, T.I. et al. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat. Immunol. 6, 515–523 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Kopcow, H.D. et al. Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc. Natl. Acad. Sci. USA 102, 15563–15568 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Parham, P. NK cells and trophoblasts: partners in pregnancy. J. Exp. Med. 200, 951–955 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Li, X.F. et al. Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells. J. Clin. Endocrinol. Metab. 86, 1823–1834 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Trundley, A. & Moffett, A. Human uterine leukocytes and pregnancy. Tissue Antigens 63, 1–12 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Tayade, C., Black, G.P., Fang, Y. & Croy, B.A. Differential gene expression in endometrium, endometrial lymphocytes, and trophoblasts during successful and abortive embryo implantation. J. Immunol. 176, 148–156 (2006).

    CAS  Article  Google Scholar 

  41. 41

    Henderson, T.A., Saunders, P.T., Moffett-King, A., Groome, N.P. & Critchley, H.O. Steroid receptor expression in uterine natural killer cells. J. Clin. Endocrinol. Metab. 88, 440–449 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Parham, P. Killer cell immunoglobulin-like receptor diversity: balancing signals in the natural killer cell response. Immunol. Lett. 92, 11–13 (2004).

    CAS  Article  Google Scholar 

  43. 43

    Coudert, J.D. et al. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 106, 1711–1717 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Pazmany, L. et al. Human leucocyte antigen-G and its recognition by natural killer cells. J. Reprod. Immunol. 43, 127–137 (1999).

    CAS  Article  Google Scholar 

  45. 45

    Kitaya, K. et al. IL-15 expression at human endometrium and decidua. Biol. Reprod. 63, 683–687 (2000).

    CAS  Article  Google Scholar 

  46. 46

    Verma, S., Hiby, S.E., Loke, Y.W. & King, A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol. Reprod. 62, 959–968 (2000).

    CAS  Article  Google Scholar 

  47. 47

    Faust, Z., Laskarin, G., Rukavina, D. & Szekeres-Bartho, J. Progesterone-induced blocking factor inhibits degranulation of natural killer cells. Am. J. Reprod. Immunol. 42, 71–75 (1999).

    CAS  PubMed  Google Scholar 

  48. 48

    Fehniger, T.A. et al. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101, 3052–3057 (2003).

    CAS  Article  Google Scholar 

  49. 49

    Rajagopalan, S. et al. Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biol 4, e9 (2006).

    Article  Google Scholar 

Download references


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.

Corresponding authors

Correspondence to Simcha Yagel or Ofer Mandelboim.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hanna, J., Goldman-Wohl, D., Hamani, Y. et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 12, 1065–1074 (2006).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing