Movatterモバイル変換

[0]ホーム
URL:

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Nature Medicine
  • Article
  • Published:

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

Nature Medicinevolume 12, pages1065–1074 (2006)Cite this article

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 bothin vitro andin 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.

This is a preview of subscription content,access via your institution

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

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 andin 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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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. Hanna, J. et al. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16– human natural killer cells.Blood102, 1569–1577 (2003).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  12. Tabiasco, J. et al. Human decidual NK cells: unique phenotype and functional properties – a review.Placenta27 (Suppl. 1), 34–39 (2006).

    Article  Google Scholar 

  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).

    Article CAS  Google Scholar 

  14. Leonard, S. et al. Mechanisms regulating immune cell contributions to spiral artery modification – facts and hypotheses – a review.Placenta27 (Suppl. 1), 40–46 (2006).

    Article  Google Scholar 

  15. Monk, J.M., Leonard, S., McBey, B.A. & Croy, B.A. Induction of murine spiral artery modification by recombinant human interferon-gamma.Placenta26, 835–838 (2005).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  19. Moffett, A. & Loke, Y.W. The immunological paradox of pregnancy: a reappraisal.Placenta25, 1–8 (2004).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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. Corthay, A. et al. Primary antitumor immune response mediated by CD4+ T cells.Immunity22, 371–383 (2005).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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. USA100, 8856–8861 (2003).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  34. Mandelboim, O. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells.Nature409, 1055–1060 (2001).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  36. Kopcow, H.D. et al. Human decidual NK cells form immature activating synapses and are not cytotoxic.Proc. Natl. Acad. Sci. USA102, 15563–15568 (2005).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  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. Trundley, A. & Moffett, A. Human uterine leukocytes and pregnancy.Tissue Antigens63, 1–12 (2004).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  43. Coudert, J.D. et al. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.Blood106, 1711–1717 (2005).

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

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

    Article CAS  Google Scholar 

  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).

    Article CAS  Google Scholar 

  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. 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.Blood101, 3052–3057 (2003).

    Article CAS  Google Scholar 

  49. Rajagopalan, S. et al. Activation of NK cells by an endocytosed receptor for soluble HLA-G.PLoS Biol4, e9 (2006).

    Article  Google Scholar 

Download references

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

Author notes

  1. Debra Goldman-Wohl and Ofer Mandelboim: These authors contributed equally to this work.

Authors and Affiliations

  1. The Lautenberg Center for General and Tumor Immunology, The Hebrew University–Hadassah Medical School, Jerusalem, 91120, Israel

    Jacob Hanna, Leonor Cohen-Daniel, Tal I Arnon, Irit Manaster, Roi Gazit & Ofer Mandelboim

  2. Department of Obstetrics and Gynecology, Hadassah University Hospital–Mount Scopus, Jerusalem, 91120, Israel

    Debra Goldman-Wohl, Yaron Hamani, Caryn Greenfield, Shira Natanson-Yaron & Simcha Yagel

  3. Department of Molecular Biology, Hadassah Medical School, Jerusalem, 91120, Israel

    Inbal Avraham & Eli Keshet

  4. Department of Pathology, Hadassah University Hospital, Jerusalem, 91120, Israel

    Diana Prus

  5. Department of Urology, Hadassah University Hospital, Jerusalem, 91120, Israel

    Vladimir Yutkin

  6. Department of Pathology, Ben Gurion University, Beer Sheva, 92865, Israel

    Daniel Benharroch

  7. Department of Microbiology and Immunology, Ben Gurion University, Beer Sheva, 92865, Israel

    Angel Porgador

Authors
  1. Jacob Hanna

    You can also search for this author inPubMed Google Scholar

  2. Debra Goldman-Wohl

    You can also search for this author inPubMed Google Scholar

  3. Yaron Hamani

    You can also search for this author inPubMed Google Scholar

  4. Inbal Avraham

    You can also search for this author inPubMed Google Scholar

  5. Caryn Greenfield

    You can also search for this author inPubMed Google Scholar

  6. Shira Natanson-Yaron

    You can also search for this author inPubMed Google Scholar

  7. Diana Prus

    You can also search for this author inPubMed Google Scholar

  8. Leonor Cohen-Daniel

    You can also search for this author inPubMed Google Scholar

  9. Tal I Arnon

    You can also search for this author inPubMed Google Scholar

  10. Irit Manaster

    You can also search for this author inPubMed Google Scholar

  11. Roi Gazit

    You can also search for this author inPubMed Google Scholar

  12. Vladimir Yutkin

    You can also search for this author inPubMed Google Scholar

  13. Daniel Benharroch

    You can also search for this author inPubMed Google Scholar

  14. Angel Porgador

    You can also search for this author inPubMed Google Scholar

  15. Eli Keshet

    You can also search for this author inPubMed Google Scholar

  16. Simcha Yagel

    You can also search for this author inPubMed Google Scholar

  17. Ofer Mandelboim

    You can also search for this author inPubMed Google Scholar

Contributions

J.H. conceived the idea for this project, designed all experiments, performed NK cell isolations, gene arrays and allin vitro andin 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 within 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 toSimcha Yagel orOfer 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)

Rights 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 Med12, 1065–1074 (2006). https://doi.org/10.1038/nm1452

Download citation

Access through your institution
Buy or subscribe

Associated content

Killers become builders during pregnancy

  • Philippe Le Bouteiller
  • Julie Tabiasco
Nature MedicineNews & Views

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature 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
[8]ページ先頭
©2009-2025 Movatter.jp