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Journal of Molecular Medicine

, Volume 90, Issue 2, pp 175–186 | Cite as

The imbalance of Th17/Th1/Tregs in patients with type 2 diabetes: relationship with metabolic factors and complications

  • Chun Zeng
  • Xiaoyun Shi
  • Baojun Zhang
  • He Liu
  • Lianjun Zhang
  • Wenjun DingEmail author
  • Yong ZhaoEmail author
Original Article

Abstract

Immune disorders are linked to the development of type 2 diabetes (T2D) and its complications. The relationship of CD4+CD25hi T regulatory cells (Treg) and pro-inflammatory Th17 and Th1 subsets in T2D patients with metabolic disorders and complications need to be determined. The ratios of CD4+CD25hi Treg/Th17 cells and CD4+CD25hi Treg/Th1 cells, but not Th17/Th1 cells, were significantly decreased in T2D patients. The thymic output CD4+Foxp3+Helios+ Tregs were normal but peripheral induced CD4+Foxp3+Helios Tregs were decreased in T2D patients. The Bcl-2/Bax ratio decreased in CD4+CD25hi Tregs in T2D patients, supporting the increased sensitivity to cell death of these cells in T2D. CD4+CD25hiCD127 Tregs in T2D patients with microvascular complications were significantly less than T2D patients with macrovascular complications. Importantly, CD4+CD25hiCD127 Tregs were positively correlated with plasma IL-6, whereas IL-17+CD4+cells were negatively related to high-density lipoprotein (HDL). Our data offered evidence for the skewed balance of anti- and pro-inflammatory T cell subsets in T2D patients and identified that HDL closely modulate T cell polarization. These results opened an alternative explanation for the substantial activation of immune cells as well as the development of T2D and complications, which may have significant impacts on the prevention and treatment of T2D patients.

Keywords

Type 2 diabetes CD4+CD25+ T regulatory cells Th17 Th1 Immune tolerance High-density lipoprotein 

Abbreviations

CPM

Counts per minute

FBS

Fetal bovine serum

FCM

Flow cytometry

FITC

Fluorescein isothiocyanate

Foxp3

Forkhead box P3

Th

T helper cells

mAbs

Monoclonal antibodies

MMC

Mitomycin C

PBMCs

Peripheral blood mononuclear cells

PE

Phycoerythrin

PI

Propidium iodide

Teff

T effector cells

PMA

Phorbol-12-myristate-13-acetate

Treg

T regulatory cells

T2D

Type 2 diabetes

CTL

Control

WBC

White blood cells

HbA1c

Hemoglobin A1c

HDL

High-density lipoprotein

LDL

Low-density lipoprotein

HLA

Human leucocyte antigen

Notes

Acknowledgments

The authors wish to thank Ms. Jing Wang, Ms. Jianxia Peng, and Mr. Cunsheng Zhang for their expert technical assistance, and Ms. Qinghuan Li for excellent laboratory management. This work was supported by grants from the National Basic Research Program of China (973 program, 2010CB945301, YZ) and the National Natural Science Foundation for Key Project (C30630060, Y.Z.).

Supplementary material

109_2011_816_MOESM1_ESM.doc (712 kb)
ESM 1 (DOC 712 kb)

References

  1. 1.
    Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846PubMedCrossRefGoogle Scholar
  2. 2.
    Kolb H, Mandrup-Poulsen T (2005) An immune origin of type 2 diabetes? Diabetologia 48:1038–1050PubMedCrossRefGoogle Scholar
  3. 3.
    Groop L, Groop PH, Koskimies S (1986) Relationship between B-cell function and HLA antigens in patients with type 2 (non-insulin-dependent) diabetes. Diabetologia 29:757–760PubMedCrossRefGoogle Scholar
  4. 4.
    Tuomilehto-Wolf E, Tuomilehto J, Hitman GA, Nissinen A, Stengard J, Pekkanen J, Kivinen P, Kaarsalo E, Karvonen MJ (1993) Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region. BMJ 307:155–159PubMedCrossRefGoogle Scholar
  5. 5.
    Fernandez-Real JM, Gutierrez C, Ricart W, Casamitjana R, Fernandez-Castaner M, Vendrell J, Richart C, Soler J (1997) The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. Diabetes 46:1468–1472PubMedCrossRefGoogle Scholar
  6. 6.
    Fernandez-Real JM, Vendrell J, Ricart W, Broch M, Gutierrez C, Casamitjana R, Oriola J, Richart C (2000) Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients. Diabetes Care 23:831–837PubMedCrossRefGoogle Scholar
  7. 7.
    Rosmond R, Chagnon M, Bouchard C, Bjorntorp P (2003) Increased abdominal obesity, insulin and glucose levels in nondiabetic subjects with a T29C polymorphism of the transforming growth factor-beta1 gene. Horm Res 59:191–194PubMedCrossRefGoogle Scholar
  8. 8.
    Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C (2007) Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin Pract 77:47–57PubMedCrossRefGoogle Scholar
  9. 9.
    Andriankaja OM, Barros SP, Moss K, Panagakos FS, DeVizio W, Beck J, Offenbacher S (2009) Levels of serum interleukin (IL)-6 and gingival crevicular fluid of IL-1beta and prostaglandin E(2) among non-smoking subjects with gingivitis and type 2 diabetes. J Periodontol 80:307–316PubMedCrossRefGoogle Scholar
  10. 10.
    Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52:812–817PubMedCrossRefGoogle Scholar
  11. 11.
    Mandrup-Poulsen T (2010) IAPP boosts islet macrophage IL-1 in type 2 diabetes. Nat Immunol 11:881–883PubMedCrossRefGoogle Scholar
  12. 12.
    Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356:1517–1526PubMedCrossRefGoogle Scholar
  13. 13.
    Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z et al (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11:897–904PubMedCrossRefGoogle Scholar
  14. 14.
    Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352PubMedCrossRefGoogle Scholar
  15. 15.
    Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8:337–348PubMedCrossRefGoogle Scholar
  16. 16.
    Yang H, Youm YH, Vandanmagsar B, Ravussin A, Gimble JM, Greenway F, Stephens JM, Mynatt RL, Dixit VD (2010) Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J Immunol 185:1836–1845PubMedCrossRefGoogle Scholar
  17. 17.
    Miller AM, Asquith DL, Hueber AJ, Anderson LA, Holmes WM, McKenzie AN, Xu D, Sattar N, McInnes IB, Liew FY (2010) Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res 107:650–658PubMedCrossRefGoogle Scholar
  18. 18.
    Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun D, Skurk T et al (2008) T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol 28:1304–1310PubMedCrossRefGoogle Scholar
  19. 19.
    Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929PubMedCrossRefGoogle Scholar
  20. 20.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedCrossRefGoogle Scholar
  21. 21.
    Jagannathan M, McDonnell M, Liang Y, Hasturk H, Hetzel J, Rubin D, Kantarci A, Van Dyke TE, Ganley-Leal LM, Nikolajczyk BS (2011) Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 53:1461–1471CrossRefGoogle Scholar
  22. 22.
    Kim SY, Johnson MA, McLeod DS, Alexander T, Hansen BC, Lutty GA (2005) Neutrophils are associated with capillary closure in spontaneously diabetic monkey retinas. Diabetes 54:1534–1542PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang L, Zhao Y (2007) The regulation of Foxp3 expression in regulatory CD4(+)CD25(+)T cells: multiple pathways on the road. J Cell Physiol 211:590–597PubMedCrossRefGoogle Scholar
  24. 24.
    Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, Ziegler SF (2003) Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25 T cells. J Clin Invest 112:1437–1443PubMedGoogle Scholar
  25. 25.
    Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184:3433–3441PubMedCrossRefGoogle Scholar
  26. 26.
    Verhagen J, Wraith DC (2010) Comment on “Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells”. J Immunol 185:7129, author reply 30PubMedCrossRefGoogle Scholar
  27. 27.
    Nichols GA, Arondekar B, Herman WH (2008) Complications of dysglycemia and medical costs associated with nondiabetic hyperglycemia. Am J Manag Care 14:791–798PubMedGoogle Scholar
  28. 28.
    Das SK, Elbein SC (2006) The Genetic Basis of Type 2 Diabetes. Cellscience 2:100–131PubMedGoogle Scholar
  29. 29.
    Pickup JC, Chusney GD, Thomas SM, Burt D (2000) Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci 67:291–300PubMedCrossRefGoogle Scholar
  30. 30.
    Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7PubMedCrossRefGoogle Scholar
  31. 31.
    Fujimoto M, Nakano M, Terabe F, Kawahata H, Ohkawara T, Han Y, Ripley B, Serada S, Nishikawa T, Kimura A, Nomura S, Kishimoto T, Naka T (2011) The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. J Immunol 186:32–40PubMedCrossRefGoogle Scholar
  32. 32.
    Devaraj S, Dasu MR, Jialal I (2010) Diabetes is a proinflammatory state: a translational perspective. Expert Rev Endocrinol Metab 5:19–28PubMedGoogle Scholar
  33. 33.
    Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83:461S–465SPubMedGoogle Scholar
  34. 34.
    Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 104:19446–19451PubMedCrossRefGoogle Scholar
  35. 35.
    Liu G, Ma H, Qiu L, Li L, Cao Y, Ma J, Zhao Y (2011) Phenotypic and functional switch of macrophages induced by regulatory CD4+CD25+ T cells in mice. Immunol Cell Biol 89:130–142PubMedCrossRefGoogle Scholar
  36. 36.
    Lopes-Virella MF, Virella G (2003) The role of immune and inflammatory processes in the development of macrovascular disease in diabetes. Front Biosci 8:s750–s768PubMedCrossRefGoogle Scholar
  37. 37.
    Westcott DJ, Delproposto JB, Geletka LM, Wang T, Singer K, Saltiel AR, Lumeng CN (2009) MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity. J Exp Med 206:3143–3156PubMedCrossRefGoogle Scholar
  38. 38.
    Wueest S, Rapold RA, Schumann DM, Rytka JM, Schildknecht A, Nov O, Chervonsky AV, Rudich A, Schoenle EJ, Donath MY et al (2010) Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J Clin Invest 120:191–202PubMedCrossRefGoogle Scholar
  39. 39.
    Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823PubMedCrossRefGoogle Scholar
  40. 40.
    Aronson D (2008) Hyperglycemia and the pathobiology of diabetic complications. Adv Cardiol 45:1–16PubMedCrossRefGoogle Scholar
  41. 41.
    Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920PubMedCrossRefGoogle Scholar
  42. 42.
    Peloso GM, Demissie S, Collins D, Mirel DB, Gabriel SB, Cupples LA, Robins SJ, Schaefer EJ, Brousseau ME (2010) Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease. J Lipid Res 51:3524–3532PubMedCrossRefGoogle Scholar
  43. 43.
    Rein P, Saely CH, Beer S, Vonbank A, Drexel H (2010) Roles of the metabolic syndrome, HDL cholesterol, and coronary atherosclerosis in subclinical inflammation. Diabetes Care 33:1853–1855PubMedCrossRefGoogle Scholar
  44. 44.
    Vaziri ND, Navab M, Fogelman AM (2010) HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol 6:287–296PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of SciencesBeijingChina
  2. 2.College of Life Science, Graduate University of Chinese Academy of SciencesBeijingChina
  3. 3.General Hospital of Chinese People’s Armed Police ForcesBeijingChina

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