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Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

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Abstract

Decidual natural killer (dNK) cells express an array of activation receptors to regulate placental immunity and development during early pregnancy. We investigated the functional character of human dNK cells during the first and second trimester of gestation and the interaction between dNK and trophoblast cells. Although the frequency of CD56+CD16− dNK among the total CD45+ leukocytes did not change over this period, the expression of the activating receptors, NKp80 and NKG2D, was greatly upregulated. We observed a significantly higher number of extravillous trophoblast cells in proximity to the dNK cells in the first trimester in comparison with the second trimester decidua. NKG2D expression by first trimester dNK cells was decreased when co-cultured with the HTR-8 trophoblast cell line. In the second trimester, functional markers of dNK activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable despite an increase in NKp80 or NKG2D surface expression. Furthermore, the degranulation capacity of dNK cells, as assessed by CD107a, was decreased in the second trimester. We suggest that in the first trimester, trophoblast–dNK interactions generate a population of dNK cells with a suppressed activating phenotype. In the second trimester, the loss of trophoblast–dNK interactions led to the inhibition of dNK cell function, although their activating receptor expression was increased. We speculate that during pregnancy, two mechanisms operate to modulate the dNK cell activation:suppression of activating receptor levels in the first trimester by trophoblasts and disengagement of receptor–ligand coupling in the second trimester.

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References

  1. King A, Burrows T, Verma S, Hiby S, Loke YW . Human uterine lymphocytes. Hum Reprod Update 1998; 4: 480–485.

    Article  CAS  Google Scholar 

  2. Moffett A, Regan L, Braude P . Natural killer cells, miscarriage, and infertility. BMJ 2004; 329: 1283–1285.

    Article  Google Scholar 

  3. Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL . Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 2009; 174: 1959–1971.

    Article  CAS  Google Scholar 

  4. Bulmer JN, Lash GE . Human uterine natural killer cells: a reappraisal. Mol Immunol 2005; 42: 511–521.

    Article  CAS  Google Scholar 

  5. Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12: 1065–1074.

    Article  CAS  Google Scholar 

  6. Moffett A, Colucci F . Uterine NK cells: active regulators at the maternal-fetal interface. J Clin Invest 2014; 124: 1872–1879.

    Article  CAS  Google Scholar 

  7. Fu B, Li X, Sun R, Tong X, Ling B, Tian Z et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal–fetal interface. Proc Natl Acad Sci USA 2013; 110: E231–E240.

    Article  CAS  Google Scholar 

  8. Williams PJ, Searle RF, Robson SC, Innes BA, Bulmer JN . Decidual leucocyte populations in early to late gestation normal human pregnancy. J Reprod Immunol 2009; 82: 24–31.

    Article  CAS  Google Scholar 

  9. Bulmer JN, Williams PJ, Lash GE . Immune cells in the placental bed. Int J Dev Biol 2010; 54: 281–294.

    Article  Google Scholar 

  10. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011; 331: 44–49.

    Article  CAS  Google Scholar 

  11. Wang F, Zhou Y, Fu B, Wu Y, Zhang R, Sun R et al. Molecular signatures and transcriptional regulatory networks of human immature decidual NK and mature peripheral NK cells. Eur J Immunol 2014; 44: 2771–2784.

    Article  CAS  Google Scholar 

  12. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003; 198: 1201–1212.

    Article  CAS  Google Scholar 

  13. Male V, Sharkey A, Masters L, Kennedy PR, Farrell LE, Moffett A . The effect of pregnancy on the uterine NK cell KIR repertoire. Eur J Immunol 2011; 41: 3017–3027.

    Article  CAS  Google Scholar 

  14. Marlin R, Duriez M, Berkane N, de Truchis C, Madec Y, Rey-Cuille M-A et al. Dynamic shift from CD85j/ILT-2 to NKG2D NK receptor expression pattern on human decidual NK during the first trimester of pregnancy. PLoS One 2012; 7: e30017.

    Article  CAS  Google Scholar 

  15. El Costa H, Casemayou A, Aguerre-Girr M, Rabot M, Berrebi A, Parant O et al. Critical and differential roles of NKp46- and NKp30-activating receptors expressed by uterine NK cells in early pregnancy. J Immunol 2008; 181: 3009–3017.

    Article  CAS  Google Scholar 

  16. Vacca P, Pietra G, Falco M, Romeo E, Bottino C, Bellora F et al. Analysis of natural killer cells isolated from human decidua: evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function. Blood 2006; 108: 4078–4085.

    Article  CAS  Google Scholar 

  17. Co EC, Gormley M, Kapidzic M, Rosen DB, Scott MA, Stolp HAR et al. Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy. Biol Reprod 2013; 88: 1–9.

    Article  Google Scholar 

  18. Vacca P, Moretta L, Moretta A, Mingari MC . Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol 2011; 32: 517–523.

    Article  CAS  Google Scholar 

  19. Robson A, Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD et al. Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J 2012; 26: 4876–4885.

    Article  CAS  Google Scholar 

  20. Vacca P, Cantoni C, Prato C, Fulcheri E, Moretta A, Moretta L et al. Regulatory role of NKp44, NKp46, DNAM-1 and NKG2D receptors in the interaction between NK cells and trophoblast cells. Evidence for divergent functional profiles of decidual versus peripheral NK cells. Int Immunol 2008; 20: 1395–1405.

    Article  CAS  Google Scholar 

  21. Karimi K, Arck PC . Natural Killer cells: keepers of pregnancy in the turnstile of the environment. Brain Behav Immun 2010; 24: 339–347.

    Article  CAS  Google Scholar 

  22. Zhang J, Chen Z, Smith GN, Croy BA . Natural killer cell-triggered vascular transformation: maternal care before birth? Cell Mol Immunol 2011; 8: 1–11.

    Article  Google Scholar 

  23. Brosens I, Pijnenborg R, Vercruysse L, Romero R . The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204: 193–201.

    Article  Google Scholar 

  24. Romero R, Kusanovic JP, Kim CJ . Placental bed disorders in the genesis of the great obstetrical syndromes. In: Pijnenborg R, Brosens I, Romero R (eds.) Placental Bed Disorders. Cambridge: Cambridge University Press, 2010: 271–289.

    Chapter  Google Scholar 

  25. Wallace AE, Whitley GS, Thilaganathan B, Cartwright JE . Decidual natural killer cell receptor expression is altered in pregnancies with impaired vascular remodeling and a higher risk of pre-eclampsia. J Leukoc Biol 2015; 97: 79–86.

    Article  Google Scholar 

  26. Wallace AE, Fraser R, Gurung S, Goulwara SS, Whitley GS, Johnstone AP et al. Increased angiogenic factor secretion by decidual natural killer cells from pregnancies with high uterine artery resistance alters trophoblast function. Hum Reprod 2014; 29: 652–660.

    Article  CAS  Google Scholar 

  27. Yokoyama WM, Sojka DK, Peng H, Tian Z . Tissue-resident natural killer cells. Cold Spring Harb Symp Quant Biol 2014; 78: 149–156.

    Article  Google Scholar 

  28. Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 2014; 3: e01659.

    Article  Google Scholar 

  29. Graham CH, Hawley TS, Hawley RC, MacDougall JR, Kerbel RS, Khoo N et al. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res 1993; 206: 204–211.

    Article  CAS  Google Scholar 

  30. Wallace A, Fraser R, Cartwright J . Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. Hum Reprod Update 2012; 18: 458–471.

    Article  CAS  Google Scholar 

  31. Dennehy KM, Klimosch SN, Steinle A . Cutting edge: NKp80 uses an atypical hemi-ITAM to trigger NK cytotoxicity. J Immunol 2011; 186: 657–661.

    Article  CAS  Google Scholar 

  32. Deguine J, Breart B, Lemaître F, Bousso P . Cutting edge: tumor-targeting antibodies enhance NKG2D-mediated NK cell cytotoxicity by stabilizing NK cell–tumor cell interactions. J Immunol 2012; 189: 5493–5497.

    Article  CAS  Google Scholar 

  33. Long EO, Sik Kim H, Liu D, Peterson ME, Rajagopalan S . Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013; 31: 227–258.

    Article  CAS  Google Scholar 

  34. Klimosch SN, Bartel Y, Wiemann S, Steinle A . Genetically coupled receptor–ligand pair NKp80-AICL enables autonomous control of human NK cell responses. Blood 2013; 122: 2380–2389.

    Article  CAS  Google Scholar 

  35. Apps R, Sharkey A, Gardner L, Male V, Kennedy P, Masters L et al. Ex vivo functional responses to HLA-G differ between blood and decidual NK cells. Mol Hum Reprod 2011; 17: 577–586.

    Article  CAS  Google Scholar 

  36. Cohnen A, Chiang SC, Stojanovic A, Schmidt H, Claus M, Saftig P et al. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood 2013; 122: 1411–1418.

    Article  CAS  Google Scholar 

  37. Brenner CD, King S, Przewoznik M, Wolters I, Adam C, Bornkamm GW et al. Requirements for control of B-cell lymphoma by NK cells. Eur J Immunol 2010; 40: 494–504.

    Article  CAS  Google Scholar 

  38. Reiners KS, Topolar D, Henke A, Simhadri VR, Kessler J, Sauer M et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 2013; 121: 3658–3665.

    Article  CAS  Google Scholar 

  39. Hu Y, Dutz JP, MacCalman CD, Yong P, Tan R, von Dadelszen P . Decidual NK cells alter in vitro first trimester extravillous cytotrophoblast migration: a role for IFN-γ. J Immunol 2006; 177: 8522–8530.

    Article  CAS  Google Scholar 

  40. Wang F, Zhou Y, Fu B, Wu Y, Zhang R, Sun R et al. Molecular signatures and transcriptional regulatory networks of human immature decidual NK and mature peripheral NK cells. Eur J Immunol 2014; 44: 2771–2784.

    Article  CAS  Google Scholar 

  41. Sotnikova N, Voronin D, Antsiferova Y, Bukina E . Interaction of decidual CD56+ NK with trophoblast cells during normal pregnancy and recurrent spontaneous abortion at early term of gestation. Scand J Immunol 2014; 80: 198–208.

    Article  CAS  Google Scholar 

  42. Arck PC, Hecher K . Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med 2013; 99: 548–556.

    Article  Google Scholar 

  43. Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE . Vascular-leukocyte interactions: mechanisms of human decidual spiral artery remodeling in vitro. Am J Pathol 2010; 177: 1017–1030.

    Article  CAS  Google Scholar 

  44. Pijnenborg R, Vercruysse L, Hanssens M . The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006; 27: 939–958.

    Article  CAS  Google Scholar 

  45. Zhang J, Dunk CE, Lye SJ . Sphingosine signalling regulates decidual NK cell angiogenic phenotype and trophoblast migration. Hum Reprod 2013; 28: 3026–3037.

    Article  CAS  Google Scholar 

  46. Apps R, Gardner L, Traherne J, Male V, Moffett A . Natural-killer cell ligands at the maternal–fetal interface: UL-16 binding proteins, MHC class-I chain related molecules, HLA-F and CD48. Hum Reprod 2008; 23: 2535–2548.

    Article  CAS  Google Scholar 

  47. Hedlund M, Stenqvist A-C, Nagaeva O, Kjellberg L, Wulff M, Baranov V et al. Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol 2009; 183: 340–351.

    Article  CAS  Google Scholar 

  48. Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O et al. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J Clin Invest 2013; 123: 4264–4272.

    Article  CAS  Google Scholar 

  49. Coudert JD, Zimmer J, Tomasello E, Cebecauer M, Colonna M, Vivier E et al. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 2005; 106: 1711–1717.

    Article  CAS  Google Scholar 

  50. Manaster I, Mandelboim O . The unique properties of uterine NK cells. Am J Reprod Immunol 2010; 63: 434–444.

    Article  CAS  Google Scholar 

  51. Coudert JD, Scarpellino L, Gros F, Vivier E, Held W . Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 2008; 111: 3571–3578.

    Article  CAS  Google Scholar 

  52. Le Bouteiller P . Human decidual NK cells: unique and tightly regulated effector functions in healthy and pathogen-infected pregnancies. Front Immunol 2013; 4: 404.

    Article  Google Scholar 

  53. Fauriat C, Long EO, Ljunggren H-G, Bryceson YT . Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 2010; 115: 2167–2176.

    Article  CAS  Google Scholar 

  54. Newman KC, Riley EM . Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens. Nat Rev Immunol 2007; 7: 279–291.

    Article  CAS  Google Scholar 

  55. Sojka DK, Tian Z, Yokoyama WM . Tissue-resident natural killer cells and their potential diversity. Semin Immunol 2014; 26: 127–131.

    Article  CAS  Google Scholar 

  56. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H . Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 2013; 31: 413–441.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Canadian Institutes of Health Research (CIHR) MOP82811 and MOP130550 for Dr. Stephen J. Lye. Dr. Lynda K. Harris is a BBSRC David Phillips Research Fellow. We thank the donors, the Research Centre for Women's and Infants' Health BioBank Program of Lunenfeld-Tanenbaum Research Institute (LTRI) and the Mount Sinai Hospital/University Health Network (Toronto, Canada) for providing the human specimens. We appreciate the work of Dr. Oksana Shynlova (LTRI) in critical reviewing. We thank Dr. John Kingdom and Dora Baczyk (Mount Sinai Hospital, Toronto) for kindly providing the anti-human CK7 antibody. We thank Ms. Annie Bang and Mr. Michael Parsons (LTRI, Mount Sinai Hospital) for the flow cytometric technical support.

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Authors and Affiliations

  1. Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5T 3H7, ON, Canada

    Jianhong Zhang, Caroline E Dunk, Melissa Kwan & Stephen J Lye

  2. Department of Obstetrics & Gynaecology, University of Toronto, Toronto, M5G 1L4, ON, Canada

    Caroline E Dunk & Stephen J Lye

  3. Department of Physiology, University of Toronto, Toronto, M5G 1L4, ON, Canada

    Melissa Kwan & Stephen J Lye

  4. Institute of Human Development, University of Manchester, Manchester, M13 9WL, UK

    Rebecca L Jones & Lynda K Harris

  5. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK

    Rebecca L Jones & Lynda K Harris

  6. Department of Pathology, University of Toronto, Toronto, M5G 1L4, ON, Canada

    Sarah Keating

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  1. Jianhong Zhang
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  2. Caroline E Dunk
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Correspondence to Jianhong Zhang.

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Zhang, J., Dunk, C., Kwan, M. et al. Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy. Cell Mol Immunol 14, 203–213 (2017). https://doi.org/10.1038/cmi.2015.66

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