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Understanding the role of killer cell immunoglobulin-like receptors in pregnancy complications

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Abstract

Pregnancy is a unique immunological situation in which a fetus-bearing paternal histocompatibility antigens can survive in a maternal environment without apparent rejection. To face this challenge, cells of the uterine immune system show characteristic changes in absolute number and composition during pregnancy. Particularly relevant to this process are uterine natural killer (uNK) cells and their cell surface receptors, killer immunoglobulin-like receptors (KIRs). The main purpose of this review is to outline the current body of knowledge on the involvement of KIRs in the complications of pregnancy. Implantation depends on the invasion of embryonic trophoblast cells into maternal uterine tissue and remodeling of the uterine spiral arterioles, which is essential for placental perfusion and successful pregnancy. The proper interaction between maternal KIRs and their ligands human leukocyte antigen (HLA) class I molecules, expressed by the extravillous trophoblast cells, is crucial in this process. KIRs are a complex family that includes both activator and inhibitory receptors. The activation profile is genetically determined in each individual and leads to diverse levels of functionality for NK and T cells on engagement with specific HLA class I molecules. An association between different KIR alleles and HLA molecules has been reported in pregnancy complications, supporting the idea of a relevant role of these receptors in successful pregnancy.

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References

  1. Williams Z. Inducing tolerance to pregnancy. N Engl J Med. 2012;367:1159–61 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22992082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. von Rango U. Fetal tolerance in human pregnancy--a crucial balance between acceptance and limitation of trophoblast invasion. Immunol Lett. 2008;115:21–32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18055021.

    Article  CAS  Google Scholar 

  3. Hiby SE, Apps R, Sharkey AM, Farrell LE, Gardner L, Mulder A, et al. Maternal activating KIRs protect against human reproductive failure mediated by HLA-C2. J Clin Invest. 2010;120:4102–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kennedy PR, Chazara O, Gardner L, Ivarsson MA, Farrell LE, Xiong S, et al. Activating KIR2DS4 is expressed by uterine NK cells and contributes to successful pregnancy. J ImmunolUnited States. 2016;197:4292–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nowak I, Wilczyńska K, Wilczyński JR, Malinowski A, Radwan P, Radwan M, et al. KIR, LILRB and their ligands’ genes as potential biomarkers in recurrent implantation failure. Arch Immunol Ther Exp (Warsz). 2017;65:391–9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28523429.

    Article  CAS  Google Scholar 

  6. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221:80–7 Available from: http://doi.wiley.com/10.1111/j.1749-6632.2010.05938.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta. 2014;35:241–8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24581729.

    Article  CAS  PubMed  Google Scholar 

  8. von Rango U, Classen-Linke I, Kertschanska S, Kemp B, Beier HM. Effects of trophoblast invasion on the distribution of leukocytes in uterine and tubal implantation sites. Fertil Steril. 2001;76:116–24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11438329.

    Article  Google Scholar 

  9. Wallace AE, Fraser RCJ. Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. Hum Reprod Update. 2012;18:458–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Moffett A, Colucci F. Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction. Immunol Rev. 2015;267:283–97.

    Article  CAS  PubMed  Google Scholar 

  11. Vento-Tormo R, Efremova M, Botting RA, Turco MY, Vento-Tormo M, Meyer KB, et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature. 2018;563:347–53 Available from: http://www.nature.com/articles/s41586-018-0698-6.

    Article  CAS  PubMed  Google Scholar 

  12. Schumacher A, Brachwitz N, Sohr S, Engeland K, Langwisch S, Dolaptchieva M, et al. Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy. J Immunol. 2009;182:5488–97 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19380797.

    Article  CAS  PubMed  Google Scholar 

  13. Burton GJ, Woods AW, Jauniaux EKJ. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009;30:473–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster MFS. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest. 2004;114:744–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lash GE, Pitman H, Morgan HL, Innes BA, Agwu CNBJ. Decidual macrophages: key regulators of vascular remodeling in human pregnancy. J Leukoc Biol. 2016;100:315–25.

    Article  CAS  PubMed  Google Scholar 

  16. Choudhury RH, Dunk CE, Lye SJ, Aplin JD, Harris LK Jr. Extravillous trophoblast and endothelial cell crosstalk mediates leukocyte infiltration to the early remodeling decidual spiral Arteriole Wall. J Immunol. 2017;198:4115–28.

    Article  CAS  PubMed  Google Scholar 

  17. Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg-v.d.Voort-Maarschalk MM, Roelen DL, et al. Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells. J Reprod Immunol. 2009;82:147–56.

    Article  CAS  Google Scholar 

  18. Kikuchi-Maki A, Catina TL, Campbell KS. Cutting Edge: KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. J Immunol. 2005;174:3859–63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15778339.

  19. Hsu KC, Chida S, Geraghty DE, Dupont B. The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism. Immunol Rev. 2002;190:40–52.

    Article  CAS  PubMed  Google Scholar 

  20. Pyo CW, Guethlein LA, Vu Q, Wang R, Abi-Rached L, Norman PJ, et al. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS One. 2010;5(12):e15115.

  21. Parham P, Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat Rev Immunol. 2013;13:133–44 Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3956658&tool=pmcentrez&rendertype=abstract.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wauquier N, Padilla C, Becquart P, Leroy E, Vieillard V. Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus infection. Immunogenetics. 2010;62:767–71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20878400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheent K, Khakoo SI. Natural killer cells and hepatitis C: action and reaction. Gut. 2011;60:268–78 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20876777.

    Article  CAS  PubMed  Google Scholar 

  24. Olcese L, Cambiaggi ASG, et al. Human diversity of killer cell immunoglobulin-like receptors and disease. J Immunol. 1997;158:5083–6.

    CAS  PubMed  Google Scholar 

  25. King A, Burrows TD, Hiby SE, Bowen JM, Joseph S, Verma S, et al. Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta. 2000;21:376–87.

    Article  CAS  PubMed  Google Scholar 

  26. Kusanovic JP, Romero R, Jodicke C, Mazaki-Tovi S, Vaisbuch E, Erez O, et al. Amniotic fluid soluble human leukocyte antigen-G in term and preterm parturition, and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2009;22:1151–66 Available from: http://www.tandfonline.com/doi/full/10.3109/14767050903019684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nowak I, Malinowski A, Barcz E, Wilczyński JR, Wagner M, Majorczyk E, et al. Possible role of HLA-G, LILRB1 and KIR2DL4 gene polymorphisms in spontaneous miscarriage. Arch Immunol Ther Exp. 2016;64:505–14.

    Article  CAS  Google Scholar 

  28. Park GM, Lee S, Park B, Kim E, Shin J, Cho KAK. Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem Biophys Res Commun. 2004;313:606–11.

    Article  CAS  PubMed  Google Scholar 

  29. Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N. HLA-G: from biology to clinical benefits. Trends Immunol. 2008;29:125–32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18249584.

    Article  CAS  PubMed  Google Scholar 

  30. Rajagopalan SLE. KIR2DL4 (CD158d): an activation receptor for HLA-G. Front Immunol. 2012;3:258.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Persson G, Melsted WN, Nilsson LL, Hviid TVF. HLA class Ib in pregnancy and pregnancy-related disorders. Immunogenetics. 2017;69:581–95 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28699111.

    Article  CAS  PubMed  Google Scholar 

  32. Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol. 2003;81:199–252 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14711057.

    Article  CAS  PubMed  Google Scholar 

  33. Rajagopalan S, Bryceson YT, Kuppusamy SP, Geraghty DE, van der Meer A, Joosten I, et al. Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biol. 2006;4:e9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16366734.

    Article  CAS  PubMed  Google Scholar 

  34. Xue S, Yang J, Yao F, Xu L, Fan L. Recurrent spontaneous abortions patients have more −14 bp/+14 bp heterozygotes in the 3’UT region of the HLA-G gene in a Chinese Han population. Tissue Antigens. 2007;69(Suppl 1):153–5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17445192.

    Article  CAS  PubMed  Google Scholar 

  35. Goodridge JP, Witt CS, Christiansen FTWH. KIR2DL4 (CD158d) genotype influences expression and function in NK cells. J Immunol. 2003;171:1768–74.

    Article  CAS  PubMed  Google Scholar 

  36. Makrigiannakis A, Petsas G, Toth B, Relakis KJU. Recent advances in understanding immunology of reproductive failure. J Reprod Immunol. 2011;90:96–104.

    Article  CAS  PubMed  Google Scholar 

  37. van Bergen J, Thompson A, van der Slik A, Ottenhoff TH, Gussekloo JKF. Phenotypic and functional characterization of CD4 T cells expressing killer Ig-like receptors. J Immunol. 2004;173:6719–26.

    Article  PubMed  Google Scholar 

  38. Tilburgs T, van der Mast BJ, Nagtzaam NM, Roelen DL, Scherjon SACF. Expression of NK cell receptors on decidual T cells in human pregnancy. J Reprod Immunol. 2009;80:22–32.

    Article  CAS  PubMed  Google Scholar 

  39. Guerra N, Guillard M, Angevin E, Echchakir H, Escudier B, Moretta A, et al. Killer inhibitory receptor (CD158b) modulates the lytic activity of tumor-specific T lymphocytes infiltrating renal cell carcinomas. Blood. 2000;95:2883–9.

    CAS  PubMed  Google Scholar 

  40. Varla-Leftherioti M, Spyropoulou-Vlachou M, Niokou D, Keramitsoglou T, Darlamitsou A, Tsekoura C, et al. Natural killer (NK) cell receptors’ repertoire in couples with recurrent spontaneous abortions. Am J Reprod Immunol. 2003;49:183–91 Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12797525.

    Article  PubMed  Google Scholar 

  41. Witt CS, Goodridge J, Gerbase-DeLima MG, Daher S, Christiansen FT. Maternal KIR repertoire is not associated with recurrent spontaneous abortion. Hum Reprod. 2004;19:2653–7.

    Article  CAS  PubMed  Google Scholar 

  42. Flores AC, Marcos CY, Paladino N, Arruvito L, Williams F, Middleton D, et al. KIR receptors and HLA-C in the maintenance of pregnancy. Tissue Antigens. 2007;69(Suppl 1):112–3.

  43. Wang S, Zhao YR, Jiao YL, Wang LC, Li JF, Cui B, et al. Increased activating killer immunoglobulin-like receptor genes and decreased specific HLA-C alleles in couples with recurrent spontaneous abortion. Biochem Biophys Res Commun. 2007;360:696–701.

    Article  CAS  PubMed  Google Scholar 

  44. Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod. 2008;23:972–6.

    Article  CAS  PubMed  Google Scholar 

  45. Vargas RG, Bompeixe EP, França PP, Marques de Moraes M, da Graça Bicalho M. Activating killer cell immunoglobulin-like receptor genes’ association with recurrent miscarriage. Am J Reprod Immunol. 2009;62:34–43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19527230.

    Article  CAS  PubMed  Google Scholar 

  46. Faridi RM, Agrawal S. Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Hum Reprod. 2011;26:491–7.

    Article  CAS  PubMed  Google Scholar 

  47. Ozturk OG, Sahin G, Karacor EDZ, Kucukgoz U. Evaluation of KIR genes in recurrent miscarriage. J Assist Reprod Genet. 2012;29:933–8.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Alecsandru D, Garrido N, Vicario JL, Barrio A, Aparicio P, Requena A, et al. Maternal KIR haplotype influences live birth rate after double embryo transfer in IVF cycles in patients with recurrent miscarriages and implantation failure. Hum Reprod. 2014;29:2637–43.

    Article  CAS  PubMed  Google Scholar 

  49. Dambaeva SV, Lee DH, Sung N, Chen CY, Bao S, Gilman-Sachs A, et al. Recurrent pregnancy loss in women with killer cell immunoglobulin-like receptor KIR2DS1 is associated with an increased HLA-C2 allelic frequency. Am J Reprod Immunol. 2016;75:94–103.

    Article  CAS  PubMed  Google Scholar 

  50. Hackmon R, Koifman A, Hyodo H, Hyobo H, Glickman H, Sheiner E, et al. Reduced third-trimester levels of soluble human leukocyte antigen G protein in severe preeclampsia. Am J Obstet Gynecol. 2007;197:255.e1–5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17826409.

    Article  CAS  Google Scholar 

  51. Hackmon R, Pinnaduwage L, Zhang J, Lye SJ, Geraghty DE, Dunk CE. Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition. Am J Reprod Immunol. 2017;77:e12643 Available from: http://doi.wiley.com/10.1111/aji.12643.

    Article  CAS  Google Scholar 

  52. García-Láez V, Serra V, Bellver J, Ferro J, Vidal C, De los Santos JM, et al. Gene polymorphisms and HLA-G expression in spontaneous abortions. Med Reprod Embriol Clin. 2015;2:82–92 Available from: http://linkinghub.elsevier.com/retrieve/pii/S2340932015000341.

    Google Scholar 

  53. Klitkou L, Dahl M, Hviid TVF, Djurisic S, Piosik ZM, Skovbo P, et al. Human leukocyte antigen (HLA)-G during pregnancy part I: correlations between maternal soluble HLA-G at midterm, at term, and umbilical cord blood soluble HLA-G at term. Hum Immunol. 2015;76:254–9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25636573.

    Article  CAS  PubMed  Google Scholar 

  54. Kofod L, Lindhard A, Bzorek M, Eriksen JO, Larsen LG, Hviid TVF. Endometrial immune markers are potential predictors of normal fertility and pregnancy after in vitro fertilization. Am J Reprod Immunol. 2017;78(3):e12684. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28440588.

  55. Pfeiffer KA, Fimmers R, Engels G, van der Ven H, van der Ven K. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol Hum Reprod. 2001;7:373–8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11279300.

    Article  CAS  PubMed  Google Scholar 

  56. Emmery J, Christiansen OB, Nilsson LL, Dahl M, Skovbo P, Møller AM, et al. Associations between fetal HLA-G genotype and birth weight and placental weight in a large cohort of pregnant women - possible implications for HLA diversity. J Reprod Immunol. 2017;120:8–14 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28267635.

    Article  PubMed  Google Scholar 

  57. Moffett A, Chazara O, Colucci F, Johnson MH. Variation of maternal KIR and fetal HLA-C genes in reproductive failure: too early for clinical intervention. Reprod Biomed OnlineNetherlands. 2016;33:763–9.

    Article  CAS  PubMed  Google Scholar 

  58. Tripathi P, Naik S, Agrawal S. HLA-E and immunobiology of pregnancy. Tissue Antigens. 2006;67:207–13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16573557.

    Article  CAS  PubMed  Google Scholar 

  59. Garcia-Beltran WF, Hölzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, et al. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol. 2016;17:1067–74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27455421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by a grant from the “Centro Singular de Investigación de Galicia” and the Spanish Ministry of Economy and Competitiveness (Fondo de Investigaciones Sanitarias and Fondos FEDER, grant number PI15/00558).

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Authors and Affiliations

  1. Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain

    R. Díaz-Peña

  2. Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile

    R. Díaz-Peña

  3. IVI-RMA, Fundación IVI; INCLIVA, IIS La Fe, Valencia University, Valencia, Spain

    M. J. de los Santos

  4. Faculty of Sport Sciences and Instituto de Investigación Hospital 12 de Octubre, Universidad Europea de Madrid, Madrid, Spain

    Alejandro Lucia

  5. Inmunología, Centro de Investigaciones Biomédicas (CINBIO), Universidade de Vigo, Vigo, Spain

    P. Castro-Santos

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  4. P. Castro-Santos
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Díaz-Peña, R., de los Santos, M.J., Lucia, A. et al. Understanding the role of killer cell immunoglobulin-like receptors in pregnancy complications. J Assist Reprod Genet 36, 827–835 (2019). https://doi.org/10.1007/s10815-019-01426-9

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