Advances in Understanding the Immune Imbalance between T-Lymphocyte Subsets and NK Cells in Recurrent Spontaneous Abortion

Abstract

Recurrent spontaneous abortion is a global problem, and unexplained recurrent abortion triggered by immunological factors is an important focus of current research. Helper T lymphocytes (Th cells) and regulatory T lymphocytes (Treg cells) are central in human immune regulation and play a complex role in pregnancy. Natural killer cells (NK cells) exist in the endometrium and cooperate with T lymphocytes to create immune tolerance at the maternal-fetal interface, which is essential for successful pregnancy. This review has analyzed studies on Th17 cell, Treg cell and NK cell dysfunction and cellular imbalances which may contribute to unexplained recurrent spontaneous abortion to suggest a possible direction for future immunotherapies.

Zusammenfassung

Der habituelle Abort ist ein weltweit auftretendes Problem, und habituelle, durch immunologische Faktoren ausgelöste Aborte unklarer Genese stehen im Mittelpunkt aktueller Forschungen. T-Helfer-Lymphozyten (TH-Zellen) und regulatorische T-Lymphozyten (T-reg-Zellen) sind zentral für die menschliche Immunregulation und spielen eine komplexe Rolle in der Schwangerschaft. In der Uterusschleimhaut gibt es natürliche Killerzellen (NK-Zellen), die mit den T-Lymphozyten zusammenarbeiten, um jene maternofetale Immuntoleranz herzustellen, die für eine erfolgreiche Schwangerschaft unabdingbar ist. In diesem Übersichtsartikel werden Studien zu Funktionsstörungen von TH17-Zellen, T-reg-Zellen und NK-Zellen sowie zum Ungleichgewicht von Zellen vorgestellt. Die besprochenen Funktionsstörungen tragen möglicherweise zum Auftreten von habituellen Aborten bei und deuten auch die potenzielle Forschungsrichtung für künftige Immuntherapien an.

Key words

Th17 cells - Treg cells - decidual natural killer cells - recurrent spontaneous abortion - review

Schlüsselwörter

TH17-Zellen - T-reg Zellen - deziduale natürliche Killerzellen - habitueller Abort - Übersichtsartikel

• References

• 1 Toth B, Jeschke U, Rogenhofer N. et al. Recurrent miscarriage current concepts in diagnosis and treatment. Reprod Immunol 2010; 85: 25-32
• 2 Zheng D, Li C, Wu T. et al. Factors associated with spontaneous abortion: a cross-sectional study of Chinese populations. Reprod Health 2017; 14: 33-45
• 3 Banadakoppa M, Chauhan MS, Havemann D. Spontaneous abortion is associated with elevated systemic C5a and reduced mRNA of complement inhibitory proteins in placenta. Clin Exp Immunol 2014; 177: 743-749
• 4 Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril 2010; 93: 1234-1243
• 5 Piccinni MP, Beloni L, Livi C. et al. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 1998; 4: 1020-1024
• 6 Makrigiannakis A, Zoumakis E, Kalantaridou S. et al. Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance. Nat Immunol 2001; 2: 1018-1024
• 7 Xu C, Mao D, Holers VM. et al. A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 2000; 287: 498-501
• 8 Colucci F, Moffett A, Trowsdale J. Medawar and the immunological paradox of pregnancy: 60 years. Eur J Immunol 2014; 10: 1883-1885
• 9 Harrington LE, Hatton RD, Mangan PR. et al. Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123-1132
• 10 Stockinger B, Veldhoen M, Stockinger B. et al. Differentiation and function of Th17 T cells. Curr Opin Immunol 2007; 19: 281-286
• 11 Lombardelli L, Logiodice F, Aguerre-Girr M. et al. Interleukin-17-producing decidual CD4+ T cells are not deleterious for human pregnancy when they also produce interleukin-4. Clin Mol Allergy 2016; 14: 1
• 12 Ruocco MG, Chaouat G, Florez L. et al. Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions. Front Immunol 2014; 21: 389-399
• 13 Stockinger B, Veldhoen M, Stockinger B. et al. Differentiation and function of Th17 T cells. Curr Opin Immunol 2007; 19: 281-286
• 14 Hayashi R, Tahara T, Shiroeda H. et al. Association of genetic polymorphisms in IL17A and IL17F with gastro-duodenal diseases. J Gastrointestin Liver Dis 2012; 21: 243-249
• 15 Santarlasci V, Maggi L, Capone M. et al. TGF-beta indirectly favours the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol 2009; 39: 207-215
• 16 Solt LA, Kumar N, Nuhant P. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011; 472: 491-494
• 17 Cosmi L, De Palma R, Santarlasci V. et al. Human interleukin-17-producing cells originate from a CD161+CD4+T-cell precursor. J Exp Med 2008; 205: 1903-1916
• 18 Hirota K, Martin B, Veldhoen M. Development, regulation and functional capacities of Th17 cells. Semin Immunopathol 2010; 32: 3-16
• 19 Kimura A, Kishimoto T, Eur J. Regulator of Treg/Th17 balance. J Immunol 2010; 40: 1830-1835
• 20 Hirota K, Martin B, Veldhoen M. Development, regulation and functional capacities of Th17 cells. Semin Immunopathol 2010; 32: 3-16
• 21 Huber S, Gagliani N, Esplugues E. et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011; 34: 554-565
• 22 Wang WJ, Hao CF, Yi L. et al. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J Reprod Immunol 2010; 84: 164-170
• 23 Wang WJ, Liu FJ, Qu HM. et al. Regulation of the expression of Th17 cells and regulatory T cells by IL-27 in patients with unexplained early recurrent miscarriage. J Reprod Immunol 2013; 99: 39-45
• 24 Nakashima A, Ito M, Shima T. et al. Accumulation of IL-17-positive cells in decidua of inevitable abortion cases. Am J Reprod Immunol 2010; 64: 4-11
• 25 Najafi S, Hadinedoushan H, Eslami G. et al. Association of IL-17A and IL-17 F gene polymorphisms with recurrent pregnancy loss in Iranian women. J Assist Reprod Genet 2014; 31: 1491-1496
• 26 Nakashima A, Ito M, Yoneda S. et al. Circulating and decidual Th17 cell levels in healthy pregnancy. Am J Reprod Immunol 2010; 63: 104-109
• 27 Saito S, Nakashima A, Shima T. et al. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 2010; 63: 601-610
• 28 Sha J, Liu F, Zhai J. et al. Alteration of Th17 and Foxp3⁺ regulatory T cells in patients with unexplained recurrent spontaneous abortion before and after the therapy of hCG combined with immunoglobulin. Exp Ther Med 2017; 14: 1114-1118
• 29 Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?. Hum Reprod Update 2009; 15: 517-535
• 30 Zenclussen AC. Regulatory T cells in pregnancy. Springer Semin Immunopathol 2006; 28: 31-39
• 31 Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol 2010; 63: 445-459
• 32 Schumacher A, Poloski E, Spörke D. et al. Luteinizing hormone contributes to fetal tolerance by regulating adaptive immune responses. Am J Reprod Immunol 2014; 71: 434-440
• 33 Wang WJ, Liu FJ, Hao CF. et al. Adoptive transfer of pregnancy-induced CD4+CD25+ regulatory T cells reverses the increase in abortion rate caused by interleukin 17 in the CBA/JxBALB/c mouse model. Hum Reprod 2014; 29: 946-952
• 34 Mjösberg J, Svensson J, Johansson E. et al. Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol. J Immunol 2009; 24: 759-769
• 35 Shima T, Sasaki Y, Itoh M. et al. Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice. Reprod Immunol 2010; 85: 121-129
• 36 Arruvito L, Sanz M, Banham AH. et al. Expansion of CD4+CD25+and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. J Immunol 2007; 178: 2572-2578
• 37 van Mourik MS, Macklon NS, Heijnen CJ. Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. Leukoc Biol 2009; 85: 4-19
• 38 Zenclussen AC, Gerlof K, Zenclussen ML. Abnormal T-cell reactivityagainst paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol 2005; 166: 811-822
• 39 Sharma S. Natural killer cells and regulatory T cells in early pregnancy loss. Int J Dev Biol 2014; 58: 219-229
• 40 Jabraneferrat N, Siewiera J. The up side of decidual natural killer cells: new developments in immunology of pregnancy. [J]. Immunology 2014; 141: 490-497
• 41 Morvan MG, Champsaur M, Reizis B. et al. Chronic In Vivo Interaction of Dendritic Cells Expressing the Ligand Rae-1ε with NK Cells Impacts NKG2D Expression and Function. Immunohorizons 2017; 1: 10-19
• 42 Raulet DH. Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 2004; 5: 996-1002
• 43 Raulet DH. Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 2004; 24: 996-1002
• 44 Arnon TI, Markel G, Mandelboim O. Tumor and viral recognition by natural killer cells receptors. Semin Cancer Biol 2006; 16: 348-358
• 45 Kusumi M, Yamashita T, Fujii T. et al. Expression patterns of lectin-like natural killer receptors, inhibitory CD94/NKG2A, and activating CD94/NKG2C on decidual CD56bright natural killer cells differ from those on peripheral CD56dim natural killer cells. Reprod Immunol 2006; 70: 33-42
• 46 Kalkunte SS, Mselle TF, Norris WE. et al. Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface. Immunol 2009; 182: 4085-4092
• 47 Fukui A, Funamizu A, Fukuhara R. et al. Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss. J Obstet Gynaecol Res 2017; 43: 1678-1686
• 48 Manaster I, Mandelboim O. The unique properties of uterine NK cells. Am J Reprod Immunol 2010; 63: 434-444
• 49 Vacca P, Moretta L, Moretta A. et al. Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol 2011; 32: 517-523
• 50 Croy BA, Zhang J, Tayade C. Analysis of uterine natural killer cells in mice. Methods Mol Biol 2010; 612: 465-503
• 51 Vacca P, Mingari MC, Moretta L. Natural killer cells in human pregnancy. J Reprod Immunol 2013; 97: 14-19
• 52 Chakraborty D, Rumi MA, Soares MJ. NK cells, hypoxia and trophoblast cell differentiation. Cell Cycle 2012; 11: 2427-2430
• 53 Shenouda MM, Gillgrass A, Nham T. et al. Ex vivo expanded natural killer cells from breast cancer patients and healthy donors are highly cytotoxic against breast cancer cell lines and patient-derived tumours. Breast Cancer Res 2017; 19: 76
• 54 Saito S, Shima T, Inada K. et al. Which types of regulatory T cells play important roles in implantation and pregnancy maintenance?. Am J Reprod Immunol 2013; 69: 340-345
• 55 El Costa H, Casemayou A, Aguerre-Girr M. 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
• 56 Co EC, Gormley M, Kapidzic M. et al. Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy. Biol Reprod 2013; 88: 155
• 57 Lee JH, Ulrich B, Cho J. et al. Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol 2011; 187: 1778-1787
• 58 Wang WJ, Hao CF, Yi L. et al. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J Reprod Immunol 2010; 84: 164-170
• 59 Sereshki N, Gharagozloo M, Ostadi V. et al. Variations in T-helper 17 and Regulatory T Cells during The Menstrual Cycle in Peripheral Blood of Women with Recurrent Spontaneous Abortion. Int J Fertil Steril 2014; 8: 59-66
• 60 Hirota K, Duarte JH, Veldhoen M. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 2011; 12: 255-263
• 61 Voo KS, Wang YH, Santori FR. et al. Identification of IL-17-producing FOXP3 regulatory T cells in humans. Proc Natl Acad Sci U S A 2009; 106: 4793-4798
• 62 Damsker JM, Hansen AM, Caspi RR. Th1 and Th17 cells, Adversaries and collaborators. Ann N Y Acad Sci 2010; 1183: 211-221
• 63 Sakaguchi S, Vignali DA, Rudensky AY. et al. The plasticity and stability of regulatory T cells. Nat Rev Immunol 2013; 13: 461-467
• 64 Blois SM, Ilarregui JM, Tometten M. et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med 2007; 13: 1450-1457
• 65 Sasaki Y, Sakai M, Miyazaki S. et al. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod 2004; 10: 347-353
• 66 Vacca P, Cantoni C, Vitale M. et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci U S A 2010; 107: 11918-11941
• 67 Hsu P, Santner-Nanan B, Dahlstrom JE. et al. Altered decidual DC-SIGN⁺ antigen-presenting cells and impaired regulatory T-cell induction in preeclampsia. Am J Pathol 2012; 181: 2149-2160
• 68 Pedroza-Pacheco I, Madrigal A, Saudemont A. Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy. Cell Mol Immunol 2013; 10: 222-229
• 69 Huber S, Gagliani N, Esplugues E. et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011; 34: 554-565
• 70 Fu B, Li X, Sun R. et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A 2013; 110: E231-E240
• 71 Fu B, Li X, Sun R. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A 2013; 110: E231-E240
• 72 Korn T, Bettelli E, Oukka M. et al. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485-517