Journal of Assisted Reproduction and Genetics

, Volume 24, Issue 9, pp 379–386 | Cite as

What is the role of regulatory T cells in the success of implantation and early pregnancy?

  • Shigeru Saito
  • Tomoko Shima
  • Akitoshi Nakashima
  • Arihiro Shiozaki
  • Mika Ito
  • Yasushi Sasaki
Immunology Updates



The immune system is well controlled by the balance between immunostimulation and immunoregulation. CD4+CD25+ regulatory T (Treg) cells and an enzyme called indoleamine-2, 3-dioxygenase (IDO) mediate maternal tolerance of the allogeneic fetus. Treg cells, therefore, may prevent early pregnancy loss due to maternal ‘rejection.’


The latest understanding of tolerance during pregnancy is reviewed.

Results and conclusions

Recent data show that CD4+CD25+ Treg cells play essential roles in the induction and maintenance of tolerance, and that they augment the IDO activity in dendritic cells and macrophages. Therefore, CD4+CD25+ Treg cells and IDO enzyme may cooperate in the induction of tolerance during pregnancy. Treg deficiency is associated with very early post-implantation loss and spontaneous abortion in animal models, and low Treg levels are associated with recurrent miscarriages in humans.


CD4+CD25+ regulatory T cell CTLA-4 Decidua IDO Miscarriage Preeclampsia 


  1. 1.
    Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B. T cell awareness of paternal alloantigens during pregnancy. Science 1995;270:630–3.CrossRefGoogle Scholar
  2. 2.
    Salha O, Sharma V, Dada T, Nugent D, Rutherford AJ, Tomlinson AJ, et al. The influence of donated gametes on the incidence of hypertensive disorders of pregnancy. Hum Reprod 1999;14:2268–73.PubMedCrossRefGoogle Scholar
  3. 3.
    Toner JP, Grainger DA, Frazier LM. Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996–1998. Fertil Steril 2002;78:1038–45.PubMedCrossRefGoogle Scholar
  4. 4.
    Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531–62.CrossRefGoogle Scholar
  5. 5.
    Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003;3:199–210.PubMedCrossRefGoogle Scholar
  6. 6.
    Saito S, Nishikawa K, Morii T, Narita N, Enomoto M, Ichijo M. Expression of activation antigens CD69, HLA-DR, interleukin-2 receptor-alpha (IL-2Rα) and IL-2Rβ on T cells of human decidua at an early stage of pregnancy. Immunology 1992;75:710–2.PubMedGoogle Scholar
  7. 7.
    Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004;5:266–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Bertoja AZ, Ritter T, et al. Abnormal T-cell reactivity against 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;166:811–22.PubMedGoogle Scholar
  9. 9.
    Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281:1191–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999;189:1363–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 2002;297:1867–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Kudo Y, Boyd CA, Spyropoulou I, Redman CW, Takikawa O, Katsuki T, et al. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. J Reprod Immunol 2004;61:87–98.PubMedCrossRefGoogle Scholar
  13. 13.
    Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002;3:1097–101.PubMedCrossRefGoogle Scholar
  14. 14.
    Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Jiang SP, Vacchio MS. Multiple mechanisms of peripheral T cell tolerance to the fetal “allograft”. J Immunol 1998;160:3086–90.PubMedGoogle Scholar
  16. 16.
    Hunt JS, Vassmer D, Ferguson TA, Miller L. Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus. J Immunol 1997;158:4122–8.PubMedGoogle Scholar
  17. 17.
    Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. Macrophages and apoptotic cell clearance during pregnancy. Am J Reprod Immunol 2004;51:275–82.PubMedCrossRefGoogle Scholar
  18. 18.
    Bouteiller PL, Pizzato N, Barakonyi A, Solier C. HLA-G, pre-eclampsia, immunity and vascular events. J Reprod Immunol 2003;59:219–34.PubMedCrossRefGoogle Scholar
  19. 19.
    Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED. Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci USA 2001;98:12150–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002;2:656–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Adams KM, Yan Z, Stevens AM, Nelson JL. The changing maternal “self” hypothesis: a mechanism for maternal tolerance of the fetus. Placenta 2007;28:378–382.PubMedCrossRefGoogle Scholar
  22. 22.
    Huppertz B, Kingdom J, Caniggia I, Desoye G, Black S, Korr H, et al. Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta 2003;24:181–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Ranella A, Vassiliadis S, Mastora C, Valentina M, Dionyssopoulou E, Athanassakis I. Constitutive intracellular expression of human leukocyte antigen (HLA)-DO and HLA-DR but not HLA-DM in trophoblast cells. Hum Immunol 2005;66:43–55.PubMedCrossRefGoogle Scholar
  24. 24.
    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature 1997;390:350–1.PubMedCrossRefGoogle Scholar
  25. 25.
    Shao L, Jacobs AR, Johnson VV, Mayer L. Activation of CD8+ regulatory T cells by human placental trophoblasts. J Immunol 2005;174:7539–47.Google Scholar
  26. 26.
    Kallikourdis M, Anderson KG, Welch KA, Betz AG. Alloantigen-enhanced accumulation of CCR5+ ‘effector’ regulatory T cells in the gravid uterus. Proc Natl Acad Sci USA 2007;104:594–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Darrasse-Jeze G, Klatzmann D, Charlotte F, Salomon BL, Cohen JL. CD4+CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice. Immunol Lett 2006;102:106–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 2007;204:57–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Kim JM, Rasmussen JP, Rudensky A. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007;8:191–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Beacher-Allan C, Brown J, Freeman G, Hafler D. CD4+CD25+ high regulatory cells in human peripheral blood. J Immunol 2001;167:1245–53.Google Scholar
  31. 31.
    Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion. Mol Hum Reprod 2004;10:347–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD4+CD25+ regulatory T-cell subset. Immunology 2004;112:38–43.PubMedCrossRefGoogle Scholar
  33. 33.
    Heikkinen J, Mottonen M, Alanen A, Lassila O. Phenotype characterization of regulatory T cells in the human decidua. Clin Exp Immunol 2004;136:373–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–61.PubMedCrossRefGoogle Scholar
  35. 35.
    Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, et al. Estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol 2004;173:2227–30.PubMedGoogle Scholar
  36. 36.
    Prieto GA, Rosenstein Y. Oestradiol potentiates the suppressive function of human CD4+CD25+ regulatory T cells by promoting their proliferation. Immunology 2006;118:58–65.PubMedCrossRefGoogle Scholar
  37. 37.
    Jasper MJ, Tremellen KP, Robertson SA. Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue. Mol Hum Reprod 2006;12:301–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Venturi GM, Conway RM, Steeber DA, Tedder TF. CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover. J Immunol 2007;178:291–300.PubMedGoogle Scholar
  39. 39.
    Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol 2006;177:4488–94.PubMedGoogle Scholar
  40. 40.
    Soler D, Chapman TR, Poisson LR, Wang L, Cote-Sierra J, Ryan M, et al. CCR8 expression identifies CD4 memory T cells enriched for FOXP3+ regulatory and Th2 effector lymphocytes. J Immunol 2006;177:6940–51.PubMedGoogle Scholar
  41. 41.
    van den Heuvel M, Peralta C, Bashar S, Taylor S, Horrocks J, Croy BA. Trafficking of peripheral blood CD56bright cells to the decidualizing uterus–new tricks for old dogmas? J Reprod Immunol 2005;67:21–34.PubMedCrossRefGoogle Scholar
  42. 42.
    Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L, et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol 2006;177:4376–83.PubMedGoogle Scholar
  43. 43.
    Miwa N, Hayakawa S, Miyazaki S, Myojo S, Sasaki Y, Sakai M, et al. IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-gamma increase in normal pregnancy but decrease in spontaneous abortion. Mol Hum Reprod 2005;11:865–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Terness P, Chuang JJ, Bauer T, Jiga L, Opelz G. Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)–producing dendritic cells: too much ado about IDO. Blood 2005;105:2480–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001;194:629–44.PubMedCrossRefGoogle Scholar
  46. 46.
    Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, et al. CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 2002;196:237–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity 2004;21:503–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Garín MI, Chu C-C, Golshayan D, Cernuda-Morollón E, Wait R, Lechler RI. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 2007;109:2058–65.PubMedCrossRefGoogle Scholar
  49. 49.
    Dosiou C, Giudice LC. Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocr Rev 2005;26:44–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Petroff MG. Immune interactions at the maternal-fetal interface. J Reprod Immunol 2005;68:1–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 2005;202:231–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Yang Y, Huang CT, Huang X, Pardoll DM. Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 2004;5:508–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005;309:1380–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T, Shiozaki A, Rolinski J, Saito S. Proportion of peripheral blood and decidual CD4+CD25bright regulatory T cells in pre-eclampsia. Clin Exp Immunol 2007;149:139–145.PubMedCrossRefGoogle Scholar
  55. 55.
    Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007;445:936–40.PubMedCrossRefGoogle Scholar
  56. 56.
    Marson A, Kretscher K, Frampton GM, Jacobsen ES, Polansky JK, Macisaac KD, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007;445:931–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701–11.PubMedCrossRefGoogle Scholar
  58. 58.
    Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T, et al. Foxp3-dependent and-independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 2006;18:1197–209.PubMedCrossRefGoogle Scholar
  59. 59.
    Arruvito L, Sanz M, Banham AH, Fainboim L. Expansion of CD4+CD25+ and Foxp3+ regulatory T cells during the follicular phase of menstrual cycle: implications for human reproduction. J Immunol 2007;178:2572–8.PubMedGoogle Scholar
  60. 60.
    Miura Y, Thoburn CJ, Bright EC, Phelps ML, Shin T, Matsui EC, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 2004;104:2187–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 2005;105:735–41.PubMedCrossRefGoogle Scholar
  62. 62.
    Huan J, Culbertson N, Spencer L, Bartholomew R, Burrow GG, Chou YK, et al. Decreased FOXP3 levels in multiple sclerosis. J Neurosci Res 2005;81:45–52.PubMedCrossRefGoogle Scholar
  63. 63.
    Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007;445:766–70.PubMedCrossRefGoogle Scholar
  64. 64.
    Stallmach T, Hebisch G. Placental pathology: its impact on explaining prenatal and perinatal death. Virchows Arch 2004;445:9–16.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Shigeru Saito
    • 1
    • 2
  • Tomoko Shima
    • 1
  • Akitoshi Nakashima
    • 1
  • Arihiro Shiozaki
    • 1
  • Mika Ito
    • 1
  • Yasushi Sasaki
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity of ToyamaToyamaJapan
  2. 2.Center of Excellence (COE) 21st ProgramMoriokaJapan

Personalised recommendations