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Home / Equine Research Bank / PLoS One / Regulatory T cells in early life: comparative study of CD4+C...
PloS one2015; 10(3); e0120661; doi: 10.1371/journal.pone.0120661

Regulatory T cells in early life: comparative study of CD4+CD25high T cells from foals and adult horses.

Abstract: The immune system of mammals is subject to continuous development during the postnatal phase of life. Studies following the longitudinal development of the immune system in healthy children are limited both by ethical considerations and sample volumes. Horses represent a particular valuable large animal model for T regulatory (Treg) cells and allergy research. We have recently characterised Treg cells from horses, demonstrated their regulatory capability and showed both their expansion and induction in vitro. Insect bite hypersensitivity (IBH) is a common allergy in horses resembling atopic dermatitis and studies have shown that first exposure to allergens in adult life results in an increased incidence of IBH. The aim of the present study was to characterize circulating CD4+CD25highFoxP3+cells in foals, evaluate their suppressive capability and their in vitro induction compared to adult horses. 19 foals (age range, 1-5 months), their adult mothers and six one-year-old horses (yearlings) were included in the study. The proportion of FoxP3+ cells within the circulating CD4+CD25high population was significantly higher in foals (47%) compared to their mothers (18%) and to yearlings (26%). Treg cells from foals also displayed a higher suppressive capability. Furthermore, CD4+CD25high cells in foals could be induced in vitro from CD4+CD25- cells in a significantly higher proportion compared to mares. These cells also displayed a significantly enhanced suppressive capability. In summary these findings support the notion that exposure of horses to allergens during maturation of the immune system assists the establishment of induced (i)Treg driven tolerance.
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Publication Date: 2015-03-19 PubMed ID: 25790481PubMed Central: PMC4366079DOI: 10.1371/journal.pone.0120661Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article investigates the differences in T regulatory cells, which play a key part in the immune system, between foals and adult horses. The study finds that younger horses have a higher proportion of these cells and that they are more effective in suppression, indicating that early exposure to allergens may lead to built-in tolerance later in life.

Introduction and Objectives

  • The researchers aimed to understand how the immune system development varies between foals and adult horses. The focus was on Treg cells – these are a type of immune cell that control the body’s immune response to prevent allergic reactions and autoimmune diseases.
  • Researchers were motivated by the lack of longitudinal studies in immune system development, particularly in the context of allergies, due to ethical and sample volume constraints in human studies. Thus, they decided to use horses as a model for this research.

Methodology

  • The study categorized the participants into three groups: foals (ages 1-5 months), their adult mothers, and one-year-old horses (yearlings). They analyzed blood samples from all participants to characterize the population of Treg cells (specifically CD4+CD25highFoxP3+) and their capabilities.
  • The researchers also conducted in vitro experiments to evaluate how many Treg cells could be induced from CD4+CD25- precursor cells in both foals and adult horses.

Findings

  • The study found that foals had a significantly higher proportion of FoxP3+ cells (a subtype of Treg cells) in their blood compared to adult horses and yearlings. These Treg cells also exhibited more potent suppressive abilities.
  • In addition, researchers found that Treg cells could be more readily induced in vitro from the CD4+CD25- precursor cells in foals than the cells in adult horses. The induced Treg cells in foals also showed enhanced suppressive abilities.

Conclusions

  • Findings support the idea that early exposure to allergens helps in promoting immune tolerance in horses by favouring the development and effectiveness of Treg cells.
  • This research can potentially lead to important insights into immunology and allergy development, and could guide the development of preventive measures and treatments for allergies in not just equine subjects, but potentially also in humans.

Cite This Article

APA
Hamza E, Mirkovitch J, Steinbach F, Marti E. (2015). Regulatory T cells in early life: comparative study of CD4+CD25high T cells from foals and adult horses. PLoS One, 10(3), e0120661. https://doi.org/10.1371/journal.pone.0120661

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 10
Issue: 3
Pages: e0120661
PII: e0120661

Researcher Affiliations

Hamza, Eman
  • Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Mirkovitch, Jelena
  • Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Steinbach, Falko
  • School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Marti, Eliane
  • Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

MeSH Terms

  • Animals
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Horses
  • Hypersensitivity / immunology
  • Hypersensitivity / pathology
  • Interleukin-10 / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Leukocytes, Mononuclear / cytology
  • Male
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Time Factors

Conflict of Interest Statement

The authors have declared that no competing interests exist.

References

This article includes 40 references
  1. Prescott SL, Seroogy C. Ontogeny of immune development and its relationship to allergic diseases and asthma. Middleton's Allergy: Principles and Practice 2014; pp. 790–806.
  2. Amoah AS, Boakye DA, van Ree R, Yazdanbakhsh M. Parasitic worms and allergies in childhood: insights from population studies 2008-2013.. Pediatr Allergy Immunol 2014 May;25(3):208-17.
    pubmed: 24325393doi: 10.1111/pai.12174google scholar: lookup
  3. Lynch SV, Wood RA, Boushey H, Bacharier LB, Bloomberg GR, Kattan M, O'Connor GT, Sandel MT, Calatroni A, Matsui E, Johnson CC, Lynn H, Visness CM, Jaffee KF, Gergen PJ, Gold DR, Wright RJ, Fujimura K, Rauch M, Busse WW, Gern JE. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children.. J Allergy Clin Immunol 2014 Sep;134(3):593-601.e12.
    doi: 10.1016/j.jaci.2014.04.018pmc: PMC4151305pubmed: 24908147google scholar: lookup
  4. McLoughlin RM, Calatroni A, Visness CM, Wallace PK, Cruikshank WW, Tuzova M, Ly NP, Ruiz-Perez B, Kattan M, Bloomberg GR, Lederman H, Gern JE, Gold DR. Longitudinal relationship of early life immunomodulatory T cell phenotype and function to development of allergic sensitization in an urban cohort.. Clin Exp Allergy 2012 Mar;42(3):392-404.
    doi: 10.1111/j.1365-2222.2011.03882.xpmc: PMC4162345pubmed: 22092655google scholar: lookup
  5. Holt PG, Rowe J, Kusel M, Parsons F, Hollams EM, Bosco A, McKenna K, Subrata L, de Klerk N, Serralha M, Holt BJ, Zhang G, Loh R, Ahlstedt S, Sly PD. Toward improved prediction of risk for atopy and asthma among preschoolers: a prospective cohort study.. J Allergy Clin Immunol 2010 Mar;125(3):653-9, 659.e1-659.e7.
    pubmed: 20226300doi: 10.1016/j.jaci.2009.12.018google scholar: lookup
  6. Harris JM, Williams HC, White C, Moffat S, Mills P, Newman Taylor AJ, Cullinan P. Early allergen exposure and atopic eczema.. Br J Dermatol 2007 Apr;156(4):698-704.
    pubmed: 17263823doi: 10.1111/j.1365-2133.2006.07710.xgoogle scholar: lookup
  7. Nwaru BI, Takkinen HM, Niemelä O, Kaila M, Erkkola M, Ahonen S, Tuomi H, Haapala AM, Kenward MG, Pekkanen J, Lahesmaa R, Kere J, Simell O, Veijola R, Ilonen J, Hyöty H, Knip M, Virtanen SM. Introduction of complementary foods in infancy and atopic sensitization at the age of 5 years: timing and food diversity in a Finnish birth cohort.. Allergy 2013 Apr;68(4):507-16.
    doi: 10.1111/all.12118pubmed: 23510377google scholar: lookup
  8. Scott M, Roberts G, Kurukulaaratchy RJ, Matthews S, Nove A, Arshad SH. Multifaceted allergen avoidance during infancy reduces asthma during childhood with the effect persisting until age 18 years.. Thorax 2012 Dec;67(12):1046-51.
    doi: 10.1136/thoraxjnl-2012-202150pubmed: 22858926google scholar: lookup
  9. Strickland DH, Thomas JA, Mok D, Blank F, McKenna KL, Larcombe AN, Sly PD, Holt PG. Defective aeroallergen surveillance by airway mucosal dendritic cells as a determinant of risk for persistent airways hyper-responsiveness in experimental asthma.. Mucosal Immunol 2012 May;5(3):332-41.
    doi: 10.1038/mi.2012.13pubmed: 22354321google scholar: lookup
  10. Björnsdóttir S, Sigvaldadóttir J, Broström H, Langvad B, Sigurdsson A. Summer eczema in exported Icelandic horses: influence of environmental and genetic factors.. Acta Vet Scand 2006 May 26;48(1):3.
    pmc: PMC1513129pubmed: 16987399doi: 10.1186/1751-0147-48-3google scholar: lookup
  11. Sommer-Locher B, Endriss V, Fromm E. Various circumstances regarding initial allergen exposure and their influence on development of insect bite hypersensitivity in horses. J Equine Vet Sci 2012; 32: 158–163.
  12. Schaffartzik A, Hamza E, Janda J, Crameri R, Marti E, Rhyner C. Equine insect bite hypersensitivity: what do we know?. Vet Immunol Immunopathol 2012 Jun 30;147(3-4):113-26.
    doi: 10.1016/j.vetimm.2012.03.017pubmed: 22575371google scholar: lookup
  13. Siegal FP. Functional ontogeny of human lymphoid cells as a factor in maternal-fetal tolerance.. Am J Reprod Immunol (1980) 1981;1(2):65-8.
    pubmed: 6978080doi: 10.1111/j.1600-0897.1981.tb00018.xgoogle scholar: lookup
  14. Akdis M. Immune tolerance in allergy.. Curr Opin Immunol 2009 Dec;21(6):700-7.
    doi: 10.1016/j.coi.2009.07.012pubmed: 19700272google scholar: lookup
  15. Ryan C, Giguère S, Hagen J, Hartnett C, Kalyuzhny AE. Effect of age and mitogen on the frequency of interleukin-4 and interferon gamma secreting cells in foals and adult horses as assessed by an equine-specific ELISPOT assay.. Vet Immunol Immunopathol 2010 Jan 15;133(1):66-71.
    doi: 10.1016/j.vetimm.2009.06.010pubmed: 19616312google scholar: lookup
  16. Kachroo P, Ivanov I, Seabury AG, Liu M, Chowdhary BP, Cohen ND. Age-related changes following in vitro stimulation with Rhodococcus equi of peripheral blood leukocytes from neonatal foals.. PLoS One 2013;8(5):e62879.
    doi: 10.1371/journal.pone.0062879pmc: PMC3656898pubmed: 23690962google scholar: lookup
  17. Wagner B, Burton A, Ainsworth D. Interferon-gamma, interleukin-4 and interleukin-10 production by T helper cells reveals intact Th1 and regulatory TR1 cell activation and a delay of the Th2 cell response in equine neonates and foals.. Vet Res 2010 Jul-Aug;41(4):47.
    doi: 10.1051/vetres/2010019pmc: PMC2865874pubmed: 20374696google scholar: lookup
  18. Marti E, Gerber V, Wilson AD, Lavoie JP, Horohov D, Crameri R, Lunn DP, Antczak D, Björnsdóttir S, Björnsdóttir TS, Cunningham F, Dérer M, Frey R, Hamza E, Horin P, Heimann M, Kolm-Stark G, Olafsdóttir G, Ramery E, Russell C, Schaffartzik A, Svansson V, Torsteinsdóttir S, Wagner B. Report of the 3rd Havemeyer workshop on allergic diseases of the Horse, Hólar, Iceland, June 2007.. Vet Immunol Immunopathol 2008 Dec 15;126(3-4):351-61.
    doi: 10.1016/j.vetimm.2008.07.008pubmed: 18775570google scholar: lookup
  19. Breathnach CC, Sturgill-Wright T, Stiltner JL, Adams AA, Lunn DP, Horohov DW. Foals are interferon gamma-deficient at birth.. Vet Immunol Immunopathol 2006 Aug 15;112(3-4):199-209.
    pubmed: 16621024doi: 10.1016/j.vetimm.2006.02.010google scholar: lookup
  20. Boyd NK, Cohen ND, Lim WS, Martens RJ, Chaffin MK, Ball JM. Temporal changes in cytokine expression of foals during the first month of life.. Vet Immunol Immunopathol 2003 Mar 20;92(1-2):75-85.
    pubmed: 12628765doi: 10.1016/s0165-2427(03)00021-7google scholar: lookup
  21. Jacks S, Giguère S. Effects of inoculum size on cell-mediated and humoral immune responses of foals experimentally infected with Rhodococcus equi: a pilot study.. Vet Immunol Immunopathol 2010 Feb 15;133(2-4):282-6.
    doi: 10.1016/j.vetimm.2009.08.004pubmed: 19720402google scholar: lookup
  22. Jacks S, Giguère S, Prescott JF. In vivo expression of and cell-mediated immune responses to the plasmid-encoded virulence-associated proteins of Rhodococcus equi in foals.. Clin Vaccine Immunol 2007 Apr;14(4):369-74.
    pmc: PMC1865619pubmed: 17301216doi: 10.1128/cvi.00448-06google scholar: lookup
  23. Jacks S, Giguère S, Crawford PC, Castleman WL. Experimental infection of neonatal foals with Rhodococcus equi triggers adult-like gamma interferon induction.. Clin Vaccine Immunol 2007 Jun;14(6):669-77.
    pmc: PMC1951072pubmed: 17409222doi: 10.1128/cvi.00042-07google scholar: lookup
  24. Sponseller BA, de Macedo MM, Clark SK, Gallup JM, Jones DE. Activation of peripheral blood monocytes results in more robust production of IL-10 in neonatal foals compared to adult horses.. Vet Immunol Immunopathol 2009 Jan 15;127(1-2):167-73.
    pubmed: 18976818doi: 10.1016/j.vetimm.2008.09.013google scholar: lookup
  25. Hamza E, Steinbach F, Marti E. CD4+CD25+ T cells expressing FoxP3 in Icelandic horses affected with insect bite hypersensitivity.. Vet Immunol Immunopathol 2012 Jul 15;148(1-2):139-44.
    doi: 10.1016/j.vetimm.2011.05.033pubmed: 21700344google scholar: lookup
  26. Hamza E, Akdis CA, Wagner B, Steinbach F, Marti E. In vitro induction of functional allergen-specific CD4+ CD25high Treg cells in horses affected with insect bite hypersensitivity.. Clin Exp Allergy 2013 Aug;43(8):889-901.
    doi: 10.1111/cea.12131pubmed: 23889243google scholar: lookup
  27. Hamza E, Doherr MG, Bertoni G, Jungi TW, Marti E. Modulation of allergy incidence in icelandic horses is associated with a change in IL-4-producing T cells.. Int Arch Allergy Immunol 2007;144(4):325-37.
    pubmed: 17671392doi: 10.1159/000106459google scholar: lookup
  28. Hamza E, Gerber V, Steinbach F, Marti E. Equine CD4(+) CD25(high) T cells exhibit regulatory activity by close contact and cytokine-dependent mechanisms in vitro.. Immunology 2011 Nov;134(3):292-304.
    doi: 10.1111/j.1365-2567.2011.03489.xpmc: PMC3209569pubmed: 21977999google scholar: lookup
  29. BILLINGHAM RE, BRENT L, MEDAWAR PB. Actively acquired tolerance of foreign cells.. Nature 1953 Oct 3;172(4379):603-6.
    pubmed: 13099277doi: 10.1038/172603a0google scholar: lookup
  30. Brent L. The discovery of immunologic tolerance.. Hum Immunol 1997 Feb;52(2):75-81.
    pubmed: 9077556doi: 10.1016/s0198-8859(96)00289-3google scholar: lookup
  31. Wang G, Miyahara Y, Guo Z, Khattar M, Stepkowski SM, Chen W. "Default" generation of neonatal regulatory T cells.. J Immunol 2010 Jul 1;185(1):71-8.
    pubmed: 20498359doi: 10.4049/jimmunol.0903806google scholar: lookup
  32. 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.
    pubmed: 15032588doi: 10.1146/annurev.immunol.21.120601.141122google scholar: lookup
  33. Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee TH, Nixon DF, McCune JM. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.. Science 2008 Dec 5;322(5907):1562-5.
    doi: 10.1126/science.1164511pmc: PMC2648820pubmed: 19056990google scholar: lookup
  34. Michaëlsson J, Mold JE, McCune JM, Nixon DF. Regulation of T cell responses in the developing human fetus.. J Immunol 2006 May 15;176(10):5741-8.
    pubmed: 16670279doi: 10.4049/jimmunol.176.10.5741google scholar: lookup
  35. Schaub B, Liu J, Schleich I, Höppler S, Sattler C, von Mutius E. Impairment of T helper and T regulatory cell responses at birth.. Allergy 2008 Nov;63(11):1438-47.
    doi: 10.1111/j.1398-9995.2008.01685.xpubmed: 18925880google scholar: lookup
  36. Fujimaki W, Takahashi N, Ohnuma K, Nagatsu M, Kurosawa H, Yoshida S, Dang NH, Uchiyama T, Morimoto C. Comparative study of regulatory T cell function of human CD25CD4 T cells from thymocytes, cord blood, and adult peripheral blood.. Clin Dev Immunol 2008;2008:305859.
    pmc: PMC2547481pubmed: 18815628doi: 10.1155/2008/305859google scholar: lookup
  37. Ly NP, Ruiz-Perez B, McLoughlin RM, Visness CM, Wallace PK, Cruikshank WW, Tzianabos AO, O'Connor GT, Gold DR, Gern JE. Characterization of regulatory T cells in urban newborns.. Clin Mol Allergy 2009 Jul 8;7:8.
    doi: 10.1186/1476-7961-7-1pmc: PMC2717905pubmed: 19586545google scholar: lookup
  38. Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood.. J Immunol 2001 Jun 15;166(12):7282-9.
    pubmed: 11390478doi: 10.4049/jimmunol.166.12.7282google scholar: lookup
  39. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells.. J Immunol 2007 Feb 15;178(4):2018-27.
    pubmed: 17277105doi: 10.4049/jimmunol.178.4.2018google scholar: lookup
  40. Liu R, Zhou Q, La Cava A, Campagnolo DI, Van Kaer L, Shi FD. Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia.. Eur J Immunol 2010 Jun;40(6):1577-89.
    doi: 10.1002/eji.200939792pmc: PMC3600978pubmed: 20352624google scholar: lookup

Citations

This article has been cited 6 times.
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    doi: 10.1016/j.ocarto.2021.100193pubmed: 36474817google scholar: lookup
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  3. Witkowska-Piłaszewicz O, Pingwara R, Winnicka A. The Effect of Physical Training on Peripheral Blood Mononuclear Cell Ex Vivo Proliferation, Differentiation, Activity, and Reactive Oxygen Species Production in Racehorses.. Antioxidants (Basel) 2020 Nov 20;9(11).
    doi: 10.3390/antiox9111155pubmed: 33233549google scholar: lookup
  4. Lindenberg F, Krych L, Kot W, Fielden J, Frøkiær H, van Galen G, Nielsen DS, Hansen AK. Development of the equine gut microbiota.. Sci Rep 2019 Oct 8;9(1):14427.
    doi: 10.1038/s41598-019-50563-9pubmed: 31594971google scholar: lookup
  5. Torsteinsdottir S, Scheidegger S, Baselgia S, Jonsdottir S, Svansson V, Björnsdottir S, Marti E. A prospective study on insect bite hypersensitivity in horses exported from Iceland into Switzerland.. Acta Vet Scand 2018 Nov 3;60(1):69.
    doi: 10.1186/s13028-018-0425-1pubmed: 30390694google scholar: lookup
  6. Tallmadge RL, Wang M, Sun Q, Felippe MJB. Transcriptome analysis of immune genes in peripheral blood mononuclear cells of young foals and adult horses.. PLoS One 2018;13(9):e0202646.
    doi: 10.1371/journal.pone.0202646pubmed: 30183726google scholar: lookup
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