Skip to main content

Advertisement

SpringerLink
Log in

Generation of Functional T-Regulatory Cells in Children with Metabolic Syndrome

  • Original Article
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Recent research implies a role of decreased number and/or function of T-regulatory cells (Tregs) in low-grade inflammation associated with obesity and atherosclerosis. The enhancement of atheroprotective immunity by the expansion of Tregs could serve as a therapeutic strategy in obesity-related immunological disturbances. The aim of our study was an attempt to generate Treg cells in children with risk factors for the development of cardiovascular disease and to compare the results to those obtained in healthy subjects. The study group consisted of 30 children with metabolic syndrome (MS) and 30 controls. Conventional CD4+CD25− cells separated from the peripheral blood were converted into Treg cells with the use of CD3/CD28 antibodies and interleukin (IL)-2/transforming growth factor (TGF)-β stimulation. The expression of critical Treg molecules and cytokines was assessed at mRNA and protein levels. The percentages of Treg cells in the peripheral blood were significantly lower in the children with MS compared to the healthy subjects. After the culture with CD3/CD28 and IL-2/TGF-β we detected a significant increase in the expression of Tregs marker transcription factor FoxP3. The Tregs induced from the children with MS varied from the ones obtained in the controls in the expression of some molecules at mRNA level (e.g. IL-27, LGAL, KLF10 and NRP1) yet not in proliferation studies. For the first time, we have demonstrated the possibility of generating functional Treg cells in children with MS. The results of our study could be used in the design of therapeutic interventions in obesity associated immunologic disturbances.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

FoxP3:

Forkhead winged/helix transcription factor 3

IFN:

Interferon

IL:

Interleukin

iTreg:

Induced T-regulatory cell

MS:

Metabolic syndrome

RT-PCR:

Real-time polymerase chain reaction

TGF:

Transforming growth factor

Tregs:

T-regulatory cells

References

  • Alam MS, Kurtz CC, Rowlett RM et al (2009) CD73 is expressed by human regulatory T helper cells ans suppresses proinflammatory cytokine production and Helicobacter felis-induced gastritis in mice. J Infect Dis 199:494–504

    Article  PubMed  Google Scholar 

  • Ammirati E, Cianflone D, Banfi M et al (2010) Circulating CD4 + CD25hiCD127lo regulatory T-cell levels do not reflect the extend or severity of carotid and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 30:1832–1841

    Article  PubMed  CAS  Google Scholar 

  • Bardel E, Larousserie F, Charlot-Rabiega P et al (2008) Human CD4+CD25+FoxP3+ regulatory T cells do not constitutively express IL-35. J Immunol 181:6898–6905

    PubMed  CAS  Google Scholar 

  • Barron L, Dooms H, Hoyer KK et al (2010) Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol 185:6426–6430

    Article  PubMed  CAS  Google Scholar 

  • Cipolletta D, Kolodin D, Benoist C et al (2011) Tissular T (regs): a unique population of adipose-tissue resident FoxP3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 23:431–437

    Article  PubMed  CAS  Google Scholar 

  • Cole TJ, Bellizzi MC, Flegal KM et al (2000) Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320:1240

    Article  PubMed  CAS  Google Scholar 

  • Connelly JB, Duaso MJ, Butler G (2007) A systematic review of controlled trials of intervention to prevent childhood obesity and overweight: a realistic synthesis of the evidence. Public Health 121:510–517

    Article  PubMed  CAS  Google Scholar 

  • Czystowska M, Strauss L, Bergmann C et al (2010) Reciprocal granzyme/perforin-mediated death of human regulatory and responder T cells is regulated by interleukin-2 (IL-2). J Mol Med 88:577–588

    Article  PubMed  CAS  Google Scholar 

  • Daniels SR, Arnett DK, Eckel RH et al (2005) Overweight in children and adolescents. Pathophysiology, consequences, prevention, and treatment. Circulation 111:1999–2012

    Article  PubMed  Google Scholar 

  • de Boer OJ, van der Meer JJ, Teeling P et al (2007) Low numbers of Foxp3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions. PLoS One 2:e779

    Article  PubMed  Google Scholar 

  • Deiuliis J, Shah Z, Shah N et al (2011) Visceral adipose inflammation in obesity is associated with critical alterations in T regulatory cell numbers. PLoS One 6:e16376

    Article  PubMed  CAS  Google Scholar 

  • Dwyer KM, Hanidziar D, Putheti P et al (2010) Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant 10:2410–2420

    Article  PubMed  CAS  Google Scholar 

  • Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939

    Article  PubMed  CAS  Google Scholar 

  • Glisic S, Ehlenbach S, Jailwala P et al (2010) Inducible regulatory T cells (iTregs) from recent onset type 1 diabetes subjects show increased in vitro suppression and higher ITCH levels compared with controls. Cell Tissue Res 339:585–595

    Article  PubMed  CAS  Google Scholar 

  • Gustafson B, Hammarstedt A, Andersson CX et al (2007) Inflamed adipose tissue. A culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 27:2276–2283

    Article  PubMed  CAS  Google Scholar 

  • Ilan Y, Maron R, Tukpah AM et al (2010) Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc Natl Acad Sci USA 107:9765–9770

    Article  PubMed  CAS  Google Scholar 

  • Kleemann R, Zadelaar S, Kooistra T (2008) Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 79:360–376

    Article  PubMed  CAS  Google Scholar 

  • Langhans B, Braunschweiger I, Arndt S et al (2010) Core-specific adaptive regulatory T-cells in different outcomes of hepatitis C. Clin Sci 119:97–109

    Article  PubMed  CAS  Google Scholar 

  • Lin J, Li M, Wang Z et al (2010) The role of CD4+ CD25+ regulatory T cells in macrophage-derived foam-cell formation. J Lipid Res 51:1208–1217

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ddCT method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • Longhi MS, Meda F, Wang P et al (2008) Expansion and de novo generation of potentiatlly therapeutic regulatory T cells in patients with autoimmune hepatitis. Hepatology 47:581–591

    Article  PubMed  CAS  Google Scholar 

  • Łuczyński W, Stasiak-Barmuta A, Wawrusiewicz-Kurylonek N et al (2010) Disturbances in some gene expression in T regulatory cells separated from children with metabolic syndrome. Scand J Immunol 71:115–122

    Article  PubMed  Google Scholar 

  • Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111–2117

    Article  PubMed  CAS  Google Scholar 

  • Magnussen CH, Koskinen J, Chen W et al (2010) Pediatric metabolic syndrome predicts adulthood metabolic syndrome, subclinical atherosclerosis, and type 2 diabetes mellitus but is no better than body mass index alone: the Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study. Circulation 122:1604–1611

    Article  PubMed  Google Scholar 

  • Mor A, Luboshits G, Planer D et al (2006) Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 27:2530–2537

    Article  PubMed  CAS  Google Scholar 

  • Mor A, Planer D, Luboshits G et al (2007) Role of naturally occuring CD4+CD25+ regulatory T cells in experimental atherosclerosis. Arterioscler Thromb Vasc Biol 27:893–900

    Article  PubMed  CAS  Google Scholar 

  • Probst-Kepper M, Geffers R, Kroger A et al (2009) GARP: a key receptor controlling FOXP3 in human regulatory T cells. J Cell Mol Med 13:3343–3357

    Article  PubMed  CAS  Google Scholar 

  • Shevach EM (2009) Mechanisms of FoxP3+ T regulatory cell-mediated suppression. Immunity 30:636–645

    Article  PubMed  CAS  Google Scholar 

  • Svec P, Vasarhelyi B, Paszthy B et al (2007) Do regulatory T cells contribute to Th1 skewness in obesity? Exp Clin Endocrinol Diabetes 115:439–443

    Article  PubMed  CAS  Google Scholar 

  • Tailor AM, Peeters PH, Norat T et al (2010) An update on the prevalence of the metabolic syndrome in children and adolescents. Int J Pediatr Obes 5:202–213

    Article  PubMed  Google Scholar 

  • Taleb S, Romain M, Ramkhelawon B et al (2009) Loos of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 206:2067–2077

    Article  PubMed  CAS  Google Scholar 

  • van Es T, van Puijvelde GH, Foks AC et al (2010) Vaccination against FoxP3(+) regulatory T cells aggravates atherosclerosis. Atherosclerosis 209:74–80

    Article  PubMed  Google Scholar 

  • Wigren M, Kolbus D, Dunér P et al (2011) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 269:546–556

    Article  PubMed  CAS  Google Scholar 

  • Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929

    Article  PubMed  CAS  Google Scholar 

  • Xie JJ, Wang J, Tang TT et al (2010) The Th17/Treg functional imbalance during atherogenesis in ApoE(−/−) mice. Cytokine 49:185–193

    Article  PubMed  CAS  Google Scholar 

  • Yi H, Zhen Y, Jiang L et al (2006) The phenotypic characterization of naturally occurring regulatory CD4+ CD25+ T cells. Cell Mol Immunol 3:189–195

    PubMed  CAS  Google Scholar 

  • Zhao Z, Wu Y, Cheng M et al (2011) Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis 217:518–524

    Article  PubMed  CAS  Google Scholar 

  • Zimmet P, Alberti KG, Kaufman F et al (2007) The metabolic syndrome in children and adolescents—an IDF consensus report. Pediatr Diabetes 8:299–306

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the Polish Ministry of Science and Higher Education (grant no. N N407 160937).

Conflict of Interest

We have no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Białystok, Waszyngtona 17, 15-274, Białystok, Poland

    Włodzimierz Łuczyński, Artur Bossowski & Barbara Głowińska-Olszewska

  2. Department of Diabetology, Endocrinology and Internal Medicine, Medical University of Białystok, Białystok, Poland

    Natalia Wawrusiewicz-Kurylonek & Adam Krętowski

  3. Department of Cytogenetics, Medical University of Białystok, Białystok, Poland

    Elżbieta Iłendo

  4. Department of Clinical Immunology, Medical University of Białystok, Białystok, Poland

    Anna Stasiak-Barmuta

Authors
  1. Włodzimierz Łuczyński
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Wawrusiewicz-Kurylonek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elżbieta Iłendo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Artur Bossowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara Głowińska-Olszewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adam Krętowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Stasiak-Barmuta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Włodzimierz Łuczyński.

About this article

Cite this article

Łuczyński, W., Wawrusiewicz-Kurylonek, N., Iłendo, E. et al. Generation of Functional T-Regulatory Cells in Children with Metabolic Syndrome. Arch. Immunol. Ther. Exp. 60, 487–495 (2012). https://doi.org/10.1007/s00005-012-0198-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-012-0198-6

Keywords

Search

Navigation