Skip to main content
SpringerLink
Log in

Interaction between dendritic cells and natural killer cells during pregnancy in mice

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

A complex regulation of innate and adaptive immune responses at the maternal fetal interface promotes tolerance of trophoblast cells carrying paternally derived antigens. Such regulatory functions involve uterine dendritic cells (uDC) and natural killer (uNK) cells. The existence of a NK and DC “cross talk” has been revealed in various experimental settings; its biological significance ranging from cooperative stimulation to cell lysis. Little is known about the presence or role of NK and DC cross talk at the maternal fetal interface. The present study shows that mouse NK and DC interactions are subject to modulation by trophoblast cells in vitro. This interaction promotes a tolerogenic microenvironment characterized by downregulation of the expression of activation markers on uNK cells and uDC and dominance of Th2 cytokines. NK and DC interactions would also influence uterine cell proliferation and this process would be strongly modulated by trophoblast-derived signals. Indeed; while low proliferation rates were observed upon regular coculture allowing direct contact between uterine cells and trophoblasts, incubation in a transwell culture system markedly increased uterine cell proliferation suggesting that soluble factors are key mediators in the molecular “dialog” between the mother and the conceptus during the establishment of mouse pregnancy. Our data further reveal that the regulatory functions of trophoblast cells associated with tolerance induction are impaired in high abortion murine matings. Interestingly, we observed that secretion of interleukin-12p70 by uDC is dramatically abrogated in the presence of uNK cells. Taken together, our results provide the first evidence that a delicate balance of interactions involving NK cells, DC, and trophoblasts at the mouse maternal fetal interface supports a successful pregnancy outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

DC:

dendritic cells

NK:

natural killer cells

Tro:

trophoblast

IDO:

indoleamine 2,3 dioxigenase

References

  1. Weetman AP (1999) The immunology of pregnancy. Thyroid 9(7):643–646, Jul

    Article  PubMed  CAS  Google Scholar 

  2. Finkelman FD, Lees A, Birnbaum R, Gause WC, Morris SC (1996) Dendritic cells can present antigen in vivo in a tolerogenic or immunogenic fashion. J Immunol 157(4):1406–1414, Aug 15

    PubMed  CAS  Google Scholar 

  3. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281(5380):1191–1193, Aug 21

    Article  PubMed  CAS  Google Scholar 

  4. Gorczynski RM, Hadidi S, Yu G, Clark DA (2002) The same immunoregulatory molecules contribute to successful pregnancy and transplantation. Am J Reprod Immunol 48(1):18–26, Jul

    Article  PubMed  Google Scholar 

  5. Zhu XY, Zhou YH, Wang MY, Jin LP, Yuan MM, Li DJ (2005) Blockade of CD86 signaling facilitates a Th2 bias at the maternal–fetal interface and expands peripheral CD4+ CD25+ regulatory T cells to rescue abortion-prone fetuses. Biol Reprod 72(2):338–345, Feb

    Article  PubMed  CAS  Google Scholar 

  6. Blois S, Tometten M, Kandil J, Hagen E, Klapp BF, Margni RA, Arck PC (2005) Intercellular adhesion molecule-1/LFA-1 cross talk is a proximate mediator capable of disrupting immune integration and tolerance mechanism at the feto-maternal interface in murine pregnancies. J Immunol 174(4):1820–1829, Feb 15

    PubMed  CAS  Google Scholar 

  7. Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, Noelle RJ, Coyle A, Mellor AL, Khoury SJ, Sayegh MH (2005) A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 202(2):231–237, Jul 18

    Article  PubMed  CAS  Google Scholar 

  8. Blois SM, Alba Soto CD, Tometten M, Klapp BF, Margni RA, Arck PC (2004) Lineage, maturity, and phenotype of uterine murine dendritic cells throughout gestation indicate a protective role in maintaining pregnancy. Biol Reprod 70(4):1018–1023, Apr

    Article  PubMed  CAS  Google Scholar 

  9. Moffett-King A (2002) Natural killer cells and pregnancy. Nat Rev Immunol 2(9):656–663, Sep

    Article  PubMed  CAS  Google Scholar 

  10. Croy BA, Esadeg S, Chantakru S, van den Heuvel M, Paffaro VA, He H, Black GP, Ashkar AA, Kiso Y, Zhang J (2003) Update on pathways regulating the activation of uterine natural killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus. J Reprod Immunol 59(2):175–191, Aug

    Article  PubMed  Google Scholar 

  11. Ain R, Canham LN, Soares MJ (2003) Gestation stage-dependent intrauterine trophoblast cell invasion in the rat and mouse: novel endocrine phenotype and regulation. Dev Biol 260(1):176–190, Aug 1

    Article  PubMed  CAS  Google Scholar 

  12. Ashkar AA, Di Santo JP, Croy BA (2000) Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 192(2):259–270, Jul 17

    Article  PubMed  CAS  Google Scholar 

  13. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, Masch R, Lockwood CJ, Schachter AD, Park PJ, Strominger JL (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 198(8):1201–1212, Oct 20

    Article  PubMed  CAS  Google Scholar 

  14. Barber EM, Pollard JW (2003) The uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol 171(1):37–46, Jul 1

    PubMed  CAS  Google Scholar 

  15. Croy BA, He H, Esadeg S, Wei Q, McCartney D, Zhang J, Borzychowski A, Ashkar AA, Black GP, Evans SS, Chantakru S, van den Heuvel M, Paffaro VA Jr, Yamada AT (2003) Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. Reproduction 126(2):149–110, Aug

    Article  PubMed  CAS  Google Scholar 

  16. Guimond MJ, Luross JA, Wang B, Terhorst C, Danial S, Croy BA (1997) Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice. Biol Reprod 56(1):169–179, Jan

    Article  PubMed  CAS  Google Scholar 

  17. Yu Y, Hagihara M, Ando K, Gansuvd B, Matsuzawa H, Tsuchiya T, Ueda Y, Inoue H, Hotta T, Kato S (2001) Enhancement of human cord blood CD34+ cell-derived NK cell cytotoxicity by dendritic cells. J Immunol 166(3):1590–1600, Feb 1

    PubMed  CAS  Google Scholar 

  18. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C (2004) Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA 101(47):16606–16611, Nov 23

    Article  PubMed  CAS  Google Scholar 

  19. Piccioli D, Sbrana S, Melandri E, Valiante NM (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 195(3):335–341, Feb 4

    Article  PubMed  CAS  Google Scholar 

  20. Vitale M, Della Chiesa M, Carlomagno S, Pende D, Arico M, Moretta L, Moretta A (2005) NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood 106(2):566–571, Jul 15

    Article  PubMed  CAS  Google Scholar 

  21. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195(3):343–351, Feb 4

    Article  PubMed  CAS  Google Scholar 

  22. Hayakawa Y, Screpanti V, Yagita H, Grandien A, Ljunggren HG, Smyth MJ, Chambers BJ (2004) NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J Immunol 172(1):123–129, Jan 1

    PubMed  CAS  Google Scholar 

  23. Semino C, Angelini G, Poggi A, Rubartelli A (2005) NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 106(2):609–616, Jul 15

    Article  PubMed  CAS  Google Scholar 

  24. Kammerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, van Kooyk Y, Kampgen E (2003) Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol 162(3):887–896, Mar

    PubMed  Google Scholar 

  25. Zuckermann FA, Head JR (1986) Expression of MHC antigens on murine trophoblast and their modulation by interferon. J Immunol 137(3):846–853, Aug 1

    PubMed  CAS  Google Scholar 

  26. Blois SM, Ilarregui JM, Tometten M, Garcia M, Orsal AS, Cordo-Russo R, Toscano MA, Bianco GA, Kobelt P, Handjiski B, Tirado I, Markert UR, Klapp BF, Poirier F, Szekeres-Bartho J, Rabinovich GA, Arck PC (2007) A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med 13(12):1450–1457, Dec

    Article  PubMed  CAS  Google Scholar 

  27. Herve C, Beyne P, Jamault H, Delacoux E (1996) Determination of tryptophan and its kynurenine pathway metabolites in human serum by high-performance liquid chromatography with simultaneous ultraviolet and fluorimetric detection. J Chromatogr B Biomed Appl 675(1):157–161, Jan 12

    Article  PubMed  CAS  Google Scholar 

  28. Maquoi E, van den Brule FA, Castronovo V, Foidart JM (1997) Changes in the distribution pattern of galectin-1 and galectin-3 in human placenta correlates with the differentiation pathways of trophoblasts. Placenta 18(5–6):433–439, Jul–Aug

    Article  PubMed  CAS  Google Scholar 

  29. Lyall F, Barber A, Myatt L, Bulmer JN, Robson SC (2000) Heme oxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function. FASEB J 14(1):208–219, Jan

    PubMed  CAS  Google Scholar 

  30. Garcia MG, Tirado-Gonzalez I, Handjiski B, Tometten M, Orsal AS, Hajos SE, Fernandez N, Arck PC, Blois SM (2007) High expression of survivin and down-regulation of stat-3 characterize the feto-maternal interface in failing murine pregnancies during the implantation period. Placenta 28(7):650–657, Jul

    Article  PubMed  CAS  Google Scholar 

  31. Lutz MB, Schuler G (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 23(9):445–449, Sep

    Article  PubMed  CAS  Google Scholar 

  32. Moretta A (2005) The dialogue between human natural killer cells and dendritic cells. Curr Opin Immunol 17(3):306–311, Jun

    Article  PubMed  CAS  Google Scholar 

  33. Zitvogel L (2002) Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med 195(3):F9–F14, Feb 4

    Article  PubMed  CAS  Google Scholar 

  34. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA (2000) Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 164(7):3596–3599, Apr 1

    PubMed  CAS  Google Scholar 

  35. Kai S, Goto S, Tahara K, Sasaki A, Tone S, Kitano S (2004) Indoleamine 2,3-dioxygenase is necessary for cytolytic activity of natural killer cells. Scand J Immunol 59(2):177–182, Feb

    Article  PubMed  CAS  Google Scholar 

  36. Uckan D, Steele A, Cherry, Wang BY, Chamizo W, Koutsonikolis A, Gilbert-Barness E, Good RA (1997) Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion. Mol Hum Reprod 3(8):655–662, Aug

    Article  PubMed  CAS  Google Scholar 

  37. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189(9):1363–1372, May 3

    Article  PubMed  CAS  Google Scholar 

  38. Mellor AL, Munn DH (2001) Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. J Reprod Immunol 52(1–2):5–13, Oct–Nov

    Article  PubMed  CAS  Google Scholar 

  39. Norwitz ER, Schust DJ, Fisher SJ (2001) Implantation and the survival of early pregnancy. N Engl J Med 345(19):1400–1408, Nov 8

    Article  PubMed  CAS  Google Scholar 

  40. King A (2000) Uterine leukocytes and decidualization. Hum Reprod Update 6(1):28–36, Jan–Feb

    Article  PubMed  CAS  Google Scholar 

  41. Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL (1996) Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA 93(7):3115–3120, Apr 2

    Article  PubMed  CAS  Google Scholar 

  42. Haimovici F, Anderson DJ (1993) Cytokines and growth factors in implantation. Microsc Res Tech 25(3):201–207, Jun 15

    Article  PubMed  CAS  Google Scholar 

  43. Chard T (1995) Cytokines in implantation. Hum Reprod Update 1(4):385–396, Jul

    Article  PubMed  CAS  Google Scholar 

  44. Ferry BL, Sargent IL, Starkey PM, Redman CW (1991) Cytotoxic activity against trophoblast and choriocarcinoma cells of large granular lymphocytes from human early pregnancy decidua. Cell Immunol 132(1):140–149, Jan

    Article  PubMed  CAS  Google Scholar 

  45. Mellor AL, Chandler P, Lee GK, Johnson T, Keskin DB, Lee J, Munn DH (2002) Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy. J Reprod Immunol 57(1–2):143–150, Oct–Nov

    Article  PubMed  CAS  Google Scholar 

  46. Xu C, Mao D, Holers VM, Palanca B, Cheng AM, Molina H (2000) A critical role for murine complement regulator crry in fetomaternal tolerance. Science 287(5452):498–501, Jan 21

    Article  PubMed  CAS  Google Scholar 

  47. Girardi G, Salmon JB (2003) The role of complement in pregnancy and fetal loss. Autoimmunity 36(1):19–26, Feb

    Article  PubMed  Google Scholar 

  48. Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12(6):682–687, Jun

    Article  PubMed  CAS  Google Scholar 

  49. Baban B, Chandler P, McCool D, Marshall B, Munn DH, Mellor AL (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J Reprod Immunol 61(2):67–77, Apr

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Petra Moschansky and Ruth Pliet for technical assistance and all the members of the Psychoneuroimmunology laboratory for their valuable input. This work was supported by Charité Grants to S.M.B and P.C.A. G.B., M.G.G., and R.I.C-R were supported by the German Academic Exchange Program; A.S.O. is supported by a doctoral fellowship of Turkish Higher Education Council and S.M.B received a Habilitation Fellowship from Charité research program. S.M.B, P.C.A., and A.S. are part of the EMBIC Network of Excellence, cofinanced by the European Commission through the FP6 framework program “Life Science, Genomics, and Biotechnology for Health.”

Author information

Authors and Affiliations

  1. Charité Centrum 12 für Innere Medizin und Dermatologie, University Medicine of Berlin, Forschungshaus, BMFZ, Forum 4, Raum 2.0547, Augustenburger Platz 1, 13353, Berlin, Germany

    Sandra M. Blois, Gabriela Barrientos, Mariana G. Garcia, Arif S. Orsal, Mareike Tometten, Rosalia I. Cordo-Russo, Burghard F. Klapp & Petra C. Arck

  2. Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex, UK

    Nelson Fernández

  3. Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci-Bolognetti, University ‘La Sapienza’, Rome, Italy

    Angela Santoni

  4. Department of Transplantation Immunology, Institute for Immunology, Heidelberg, Germany

    Peter Terness

Authors
  1. Sandra M. Blois
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriela Barrientos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariana G. Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arif S. Orsal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mareike Tometten
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rosalia I. Cordo-Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Burghard F. Klapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Angela Santoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nelson Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Peter Terness
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Petra C. Arck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandra M. Blois.

Additional information

Gabriela Barrientos and Mariana G. Garcia contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blois, S.M., Barrientos, G., Garcia, M.G. et al. Interaction between dendritic cells and natural killer cells during pregnancy in mice. J Mol Med 86, 837–852 (2008). https://doi.org/10.1007/s00109-008-0342-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-008-0342-2

Keywords

Search

Navigation