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Diabetologia

, Volume 61, Issue 7, pp 1633–1643 | Cite as

A proinflammatory CD4+ T cell phenotype in gestational diabetes mellitus

  • Angela Sheu
  • Yixian Chan
  • Angela Ferguson
  • Mohammad B. Bakhtyari
  • Wendy Hawke
  • Chris White
  • Yuk Fun Chan
  • Patrick J. Bertolino
  • Heng G. Woon
  • Umaimainthan Palendira
  • Frederic Sierro
  • Sue Mei Lau
Article

Abstract

Aims/hypothesis

Numerous adaptations of the maternal immune system are necessary during pregnancy to maintain immunological tolerance to the semi-allogeneic fetus. Several complications of pregnancy have been associated with dysregulation of these adaptive mechanisms. While gestational diabetes mellitus (GDM) has been associated with upregulation of circulating inflammatory factors linked to innate immunity, polarisation of the adaptive immune system has not been extensively characterised in this condition. We aimed to characterise pro- and anti-inflammatory CD4+ (T helper [Th]) T cell subsets in women with GDM vs women without GDM (of similar BMI), during and after pregnancy, and examine the relationship between CD4+ subsets and severity of GDM.

Methods

This is a prospective longitudinal case–control study of 55 women with GDM (cases) and 65 women without GDM (controls) at a tertiary maternity hospital. Quantification of proinflammatory (Th17, Th17.1, Th1) and anti-inflammatory (regulatory T cell [Treg]) CD4+ T cell subsets was performed on peripheral blood at 37 weeks gestation and 7 weeks postpartum, and correlated with clinical characteristics and measures of blood glucose.

Results

Women with GDM had a significantly greater percentage of Th17 (median 2.49% [interquartile range 1.62–4.60] vs 1.85% [1.13–2.98], p = 0.012) and Th17.1 (3.06% [1.30–4.33] vs 1.55% [0.65–3.13], p = 0.006) cells compared with the control group of women without GDM. Women with GDM also had higher proinflammatory cell ratios (Th17:Treg, Th17.1:Treg and Th1:Treg) in pregnancy compared with the control group of women without GDM. In the control group, there was a statistically significant independent association between 1 h glucose levels in the GTT and Th17 cell percentages, and also between 2 h glucose levels and percentage of Th17 cells. The percentage of Th17 cells and the Th17:Treg ratio declined significantly after delivery in women with GDM, whereas this was not the case with the control group of women. Nevertheless, a milder inflammatory phenotype persisted after delivery (higher Th17:Treg ratio) in women with GDM vs women without.

Conclusions/interpretation

Dysregulation of adaptive immunity supports a novel paradigm of GDM that extends beyond hyperglycaemia and altered innate immunity.

Keywords

Adaptive immunity Diabetes Gestational diabetes mellitus Inflammation Pregnancy T cells Th17 

Abbreviations

GCT

Glucose challenge test

GDM

Gestational diabetes mellitus

IA-2

Islet autoantibody-2

LGA

Large for gestational age

PBMC

Peripheral blood mononuclear cell

SGA

Small for gestational age

Th

T helper

Treg

Regulatory T cell

Notes

Acknowledgements

The authors would like to thank S. L. Lau (Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW, Australia) for reviewing the manuscript and P.-A. Sierro (Les Rocailles, Heremence, Switzerland) for technical assistance.

Contribution statement

AS acquired, analysed and interpreted data and contributed to drafting the article. YC acquired, analysed and interpreted the data and revised the article. AF, MB, CW, YFC, WH, HW and PB acquired and/or interpreted data and revised the manuscript. UP interpreted data, was involved in study design and revised the article. FS and SML designed and supervised the study, acquired and analysed the data and wrote the article. All authors approved the final version of the article. FS and SML are responsible for the integrity of the work as a whole.

Funding

This study was supported by an Australasian Diabetes in Pregnancy Society research grant and a Prince of Wales Hospital Foundation grant.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4615_MOESM1_ESM.pdf (219 kb)
ESM (PDF 218 kb)

References

  1. 1.
    HAPO Study Cooperative Research Group, Metzger BE, Lowe LP et al (2008) Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358:1991–2002CrossRefGoogle Scholar
  2. 2.
    Desoye G, Hauguel-de Mouzon S (2007) The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care 30(Suppl 2):S120–S126CrossRefPubMedGoogle Scholar
  3. 3.
    Abell SK, De Courten B, Boyle JA, Teede HJ (2015) Inflammatory and other biomarkers: role in pathophysiology and prediction of gestational diabetes mellitus. Int J Mol Sci 16:13442–13473CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Fu B, Tian Z, Wei H (2014) TH17 cells in human recurrent pregnancy loss and pre-eclampsia. Cell Mol Immunol 11:564–570CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Santner-Nanan B, Peek MJ, Khanam R et al (2009) Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J Immunol 183:7023–7030CrossRefPubMedGoogle Scholar
  6. 6.
    Rahimzadeh M, Norouzian M, Arabpour F, Naderi N (2016) Regulatory T cells and preeclampsia: an overview of literature. Expert Rev Clin Immunol 12:209–227CrossRefPubMedGoogle Scholar
  7. 7.
    Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28:445–489CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ramesh R, Kozhaya L, McKevitt K et al (2014) Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211:89–104CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Heidt S, Segundo DS, Chadha R, Wood KJ (2010) The impact of Th17 cells on transplant rejection and the induction of tolerance. Curr Opin Organ Transplant 15:456–461CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Waite JC, Skokos D (2012) Th17 response and inflammatory autoimmune diseases. Int J Inflamm 2012:819467CrossRefGoogle Scholar
  11. 11.
    Hu FB, Meigs JB, Li TY, Rifai N, Manson JE (2004) Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 53:693–700CrossRefPubMedGoogle Scholar
  12. 12.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334CrossRefPubMedGoogle Scholar
  13. 13.
    Jagannathan-Bogdan M, McDonnell ME, Shin H et al (2011) Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 186:1162–1172CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao R, Tang D, Yi S et al (2014) Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PLoS One 9:e85770CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Arck PC, Hecher K (2013) Fetomaternal immune cross-talk and its consequences for maternal and offspringʼs health. Nat Med 19:548–556CrossRefPubMedGoogle Scholar
  16. 16.
    Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT (2004) Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T cell subset. Immunology 112:38–43CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yang H, Qiu L, Chen G, Ye Z, Lu C, Lin Q (2008) Proportional change of CD4+CD25+ regulatory T cells in decidua and peripheral blood in unexplained recurrent spontaneous abortion patients. Fertil Steril 89:656–661CrossRefPubMedGoogle Scholar
  18. 18.
    Lapolla A, Dalfra MG, Sanzari M et al (2005) Lymphocyte subsets and cytokines in women with gestational diabetes mellitus and their newborn. Cytokine 31:280–287CrossRefPubMedGoogle Scholar
  19. 19.
    Pendeloski KP, Mattar R, Torloni MR, Gomes CP, Alexandre SM, Daher S (2015) Immunoregulatory molecules in patients with gestational diabetes mellitus. Endocrine 50:99–109CrossRefPubMedGoogle Scholar
  20. 20.
    Mahmoud F, Abul H, Omu A, Haines D (2005) Lymphocyte sub-populations in gestational diabetes. Am J Reprod Immunol 53:21–29CrossRefPubMedGoogle Scholar
  21. 21.
    Schober L, Radnai D, Spratte J et al (2014) The role of regulatory T cell (Treg) subsets in gestational diabetes mellitus. Clin Exp Immunol 177:76–85CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445CrossRefPubMedGoogle Scholar
  23. 23.
    Maecker HT, McCoy JP, Nussenblatt R (2012) Standardizing immunophenotyping for the human immunology project. Nat Rev Immunol 12:191–200CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    He J, Zhang X, Wei Y et al (2016) Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat Med 22:991–993CrossRefPubMedGoogle Scholar
  25. 25.
    Nikolajczyk BS, Jagannathan-Bogdan M, Denis GV (2012) The outliers become a stampede as immunometabolism reaches a tipping point. Immunol Rev 249:253–275CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ip B, Cilfone NA, Belkina AC et al (2016) Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFα production. Obesity (Silver Spring) 24:102–112CrossRefGoogle Scholar
  27. 27.
    Gaffen SL (2009) Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9:556–567CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zuniga LA, Shen WJ, Joyce-Shaikh B et al (2010) IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185:6947–6959CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fabbrini E, Cella M, McCartney SA et al (2013) Association between specific adipose tissue CD4+ T cell populations and insulin resistance in obese individuals. Gastroenterology 145(366–374):e361–e363Google Scholar
  30. 30.
    Walsh NP, Gleeson M, Shephard RJ et al (2011) Position statement. Part one: Immune function and exercise. Exerc Immunol Rev 17:6–63PubMedGoogle Scholar
  31. 31.
    Dandona P, Chaudhuri A, Mohanty P, Ghanim H (2007) Anti-inflammatory effects of insulin. Curr Opin Clin Nutr Metab Care 10:511–517CrossRefPubMedGoogle Scholar
  32. 32.
    Viardot A, Grey ST, Mackay F, Chisholm D (2007) Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology 148:346–353CrossRefPubMedGoogle Scholar
  33. 33.
    Sun Q, Li J, Gao F (2014) New insights into insulin: the anti-inflammatory effect and its clinical relevance. World J Diabetes 5:89–96CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ostlund I, Haglund B, Hanson U (2004) Gestational diabetes and preeclampsia. Eur J Obstet Gynecol Reprod Biol 113:12–16CrossRefPubMedGoogle Scholar
  35. 35.
    Landon MB, Spong CY, Thom E et al (2009) A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 361:1339–1348CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Crowther CA, Hiller JE, Moss JR et al (2005) Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 352:2477–2486CrossRefPubMedGoogle Scholar
  37. 37.
    Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R (2014) Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol 10:466–480CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bellamy L, Casas JP, Hingorani AD, Williams D (2009) Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 373:1773–1779CrossRefPubMedGoogle Scholar
  39. 39.
    Shah BR, Retnakaran R, Booth GL (2008) Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care 31:1668–1669CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Nakashima A, Ito M, Yoneda S, Shiozaki A, Hidaka T, Saito S (2010) Circulating and decidual Th17 cell levels in healthy pregnancy. Am J Reprod Immunol 63:104–109CrossRefPubMedGoogle Scholar
  41. 41.
    Piccinni MP, Lombardelli L, Logiodice F, Kullolli O, Parronchi P, Romagnani S (2016) How pregnancy can affect autoimmune diseases progression? Clin Mol Allergy 14:11CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Son HJ, Lee J, Lee SY et al (2014) Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediat Inflamm 2014:973986CrossRefGoogle Scholar
  43. 43.
    Forslund K, Hildebrand F, Nielsen T et al (2015) Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–266CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mandal M, Donnelly R, Elkabes S et al (2013) Maternal immune stimulation during pregnancy shapes the immunological phenotype of offspring. Brain Behav Immun 33:33–45CrossRefPubMedGoogle Scholar
  45. 45.
    Mandal M, Marzouk AC, Donnelly R, Ponzio NM (2010) Preferential development of Th17 cells in offspring of immunostimulated pregnant mice. J Reprod Immunol 87:97–100CrossRefPubMedGoogle Scholar
  46. 46.
    Mandal M, Marzouk AC, Donnelly R, Ponzio NM (2011) Maternal immune stimulation during pregnancy affects adaptive immunity in offspring to promote development of TH17 cells. Brain Behav Immun 25:863–871CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Angela Sheu
    • 1
  • Yixian Chan
    • 1
  • Angela Ferguson
    • 2
  • Mohammad B. Bakhtyari
    • 1
  • Wendy Hawke
    • 3
  • Chris White
    • 1
    • 3
    • 4
  • Yuk Fun Chan
    • 1
  • Patrick J. Bertolino
    • 5
    • 6
  • Heng G. Woon
    • 2
  • Umaimainthan Palendira
    • 2
    • 6
  • Frederic Sierro
    • 7
    • 8
  • Sue Mei Lau
    • 1
    • 3
    • 4
  1. 1.Department of Diabetes and EndocrinologyPrince of Wales HospitalRandwickAustralia
  2. 2.Human Viral and Cancer ImmunologyCentenary InstituteCamperdownAustralia
  3. 3.The Royal Hospital for WomenRandwickAustralia
  4. 4.Prince of Wales Clinical School, UNSWRandwickAustralia
  5. 5.Liver ImmunologyCentenary InstituteCamperdownAustralia
  6. 6.Immunology, Central Clinical SchoolUniversity of SydneySydneyAustralia
  7. 7.Vascular Immunology, School of Medical SciencesUniversity of SydneySydneyAustralia
  8. 8.Human Health, Nuclear Science & Technology and Landmark Infrastructure (NSTLI)Australian Nuclear Science and Technology OrganisationSydneyAustralia

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