Sign Up Submit Enquiry

Regulatory T Lymphocyte Subpopulations in the Early Stages of Carotid Artery Stenosis

Home Regulatory T Lymphocyte Subpopulations in the Early Stages of Carotid Artery Stenosis

Related Articles

Contact us

Article Content

Abstract

The aim of this study was to evaluate the CD4+ CD25+ and LAG3+ regulatory T lymphocyte subpopulations in patients with traditional cardiovascular risk factors and increased values of intima media thickness (IMT). Based on Doppler ultrasound, 41 patients with traditional cardiovascular risk factors were divided into two groups: group H-IMT (high-intima medial thickness) including 22 subjects with intima medial thickness (IMT) 1.0 mm and group L-IMT (low-intima medial thickness) including 19 patients with IMT 1.0 mm. Considering blood pressure values, two further groups were selected: group H-IMT/AH including 13 patients by arterial hypertension (AH) with IMT values 1.0 mm and group RF (risk factors) including 10 patients with normal blood pressure values and IMT 1.0 mm. Frequencies of T CD4+, T helper 17 (Th17), regulatory T CD4+ CD25+ (Tregs) and Lag3+ (LAG3 + Tregs) lymphocyte subpopulations were evaluated. A p value 0.05 was considered significant. Our results showed that Tregs and Treg/T17 ratio were significantly reduced in the H-IMT group compared with the L-IMT group (p 0.0093 and p 0.0047, respectively). Furthermore, in the HIMT/AH group, LAG3+ Tregs were significantly increased (p 0.0378) and CD4+ CD25+ Tregs significantly reduced (p 0.04398). We therefore would suggest that in patients with traditional cardiovascular risk factors, the reduction of regulatory T lymphocyte subpopulations can favour the progression of atherosclerotic disease. In this context, the increase in Lag3+ Tregs observed in hypertensive patients showing higher IMT values suggests that inflammation may induce the expression of LAG on Tregs, amplifying the pro-inflammatory mechanisms that induce carotid plaque formation.

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

  • Atherosclerosis
  • Carotid artery disease
  • CD4-positive T cells
  • NKT cells
  • Regulatory T cells
  • T cells

Data Availability

No datasets were generated or analysed during the current study.

Code Availability

Not applicable.

Abbreviations

IMT :
Intima media thickness
AH :
Arterial hypertension
Th17 :
T helper 17
Tregs :
Regulatory T lymphocytes
LAG3 + Tregs :
Regulatory LAG3 + T lymphocytes
CAS :
Carotid artery stenosis
TIA :
Transient ischaemic attack
Th1 :
T helper1 lymphocytes
MMPs :
Matrix metalloproteinases

References

  1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2002;352:1685–95. https://doi.org/10.1056/NEJMra043430.

    Article Google Scholar

  2. Malekmohammad K, Bezsonov EE, Rafieian-Kopaei M. Role of lipid accumulation and inflammation in atherosclerosis: focus on molecular and cellular mechanisms. Front Cardiovasc Med. 2021;8:707529. https://doi.org/10.3389/fcvm.2021.707529.

    Article CAS Google Scholar

  3. Nezu T, Hosomi N. Usefulness of carotid ultrasonography for risk stratification of cerebral and cardiovascular disease. J Atheroscler Thromb. 2020. https://doi.org/10.5551/jat.RV17044.

  4. Fliatova AY, Potekhina AY, Pylaeva EA, et al. The severity of internal carotid artery stenosis is associated with the circulating Th17 level. Heliyon. 2020;6:e03856. https://doi.org/10.1016/j.heliyon.2020.e03856. eCollection2020May.

    Article Google Scholar

  5. Poznyak AV, Bezsonov EE, Popkova TV, Starodubova AV, Orekhov AN. Immunity in atherosclerosis: focusing on T and B cells. Int J Mol Sci. 2021;22:8379. https://doi.org/10.3390/ijms22168379.

    Article CAS Google Scholar

  6. Piconese S, Walker LSK, Dominguez-Villar M. Editorial: control of regulatory T cell stability, plasticity, and function in health and disease. Front Immunol. 2021;11:611591. https://doi.org/10.3389/fimmu.2020.611591.

    Article CAS Google Scholar

  7. He X, Liang B, Gu N. Th17/Treg imbalance and atherosclerosis. Dis Markers. 2020;2020:8821029. https://doi.org/10.1155/2020/8821029.

    Article CAS Google Scholar

  8. Kleinschnitz C, Kraft P, Dreykluft A et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood. 2013;121:679–91. https://doi.org/10.1182/blood-2012-04-426734.

  9. Gagliani N, Magnani CF, Huber S, et al. Co-expression of CD49b and Lag3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013;19:739–46. https://doi.org/10.1038/nm.3179. Epub 2013 Apr 28.

    Article CAS Google Scholar

  10. Ammirati E, Cianflone D, Banfi M, et al. Circulating CD4+CD25hiCD127lo regulatory T-cell levels do not reflect the extent or severity of carotid and coronary artery stenosis. Arterioscler Thromb Vasc Biol. 2010;30:1832–41. https://doi.org/10.1161/ATVBAHA.110.206813. Epub 2010 Jun 10.

    Article CAS Google Scholar

  11. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S19–40. https://doi.org/10.2337/dc23-S002.

    Article Google Scholar

  12. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2018 ACC/AHA Multisociety Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2019;73(24):e285–e350. https://doi.org/10.1016/j.jacc.2018.11.003

  13. European Society of Cardiology (ESC) and European Society of Hypertension (ESH). 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104.

  14. Hot A, Lennie V, Mussec P. Combination of IL 17 and TNF-alpha induces a proinflammatory, procoagulant e prothrombotic phenotype in human endothelial cells. Ann Rheum Dis. 2012;71:768–76. https://doi.org/10.1136/annrheumdis-2011-200468. Epub 2012 Jan 18.

    Article CAS Google Scholar

  15. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74. https://doi.org/10.1038/nature01323.

    Article CAS Google Scholar

  16. Liu Y, Zhang Y, Zhang H, et al. Cytokines associated with immune response in atherosclerosis. Front Immunol. 2023;14: 9556506. https://doi.org/10.3389/fimmu.2023.9556506.

    Article Google Scholar

  17. Stubbe T, Ebner F, Richter D, et al. Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO. J Cereb Blood Flow Metab. 2013;33:37–47. https://doi.org/10.1038/jcbfm.2012.128. Epub 2012 Sep 12.

    Article CAS Google Scholar

  18. Taleb S, Romain M, Ramkhelawon B, et al. Loss of SOCS3 expression in T cells reveals a regulatory role for IL-17 in atherosclerosis. J Exp Me. 2009;206:2067–77. https://doi.org/10.1084/jem.20090545.

    Article CAS Google Scholar

  19. Gong F, Liu Z, Liu J, Zhou P, Liu Y, Lu X. The paradoxical role of IL-17 in atherosclerosis. Cell Immunol. 2015;297:33–9. https://doi.org/10.1016/j.cellimm.2015.05.007. Epub 2015 May 29.

    Article CAS Google Scholar

  20. Del Porto F, Cifani N, Proietta M, et al. Regulatory TCD4+CD25+ lymphocytes increase in symptomatic carotid artery stenosis. Ann Med. 2017;49:283–90. https://doi.org/10.1080/07853890.2016.1241427. Epub 2016 Dec 8.

    Article CAS Google Scholar

  21. Xu X, Li M, Jiang Y. The paradox role of regulatory T cells in ischemic stroke. Scientific World Journal. 2013;2013:174373. https://doi.org/10.1155/2013/174373.

    Article CAS Google Scholar

  22. Keane C, Law SC, Gould C, et al. LAG3:a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Adv. 2020;4:1367–77. https://doi.org/10.1182/bloodadvances.2019001390.

    Article CAS Google Scholar

  23. Zhang Q, Chikina M, Szymczak-Workman AL, et al. LAG-3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci Immunol. 2017;2:1–21. https://doi.org/10.1126/sciimmunol.aah4569.

    Article Google Scholar

  24. Slevin SM, Garner LC, Lahiff C et al. Lymphocyte activation gene (LAG)-3 is associated with mucosal inflammation and disease activity in ulcerative colitis. J Crohns Colitis 2020.https://doi.org/10.1093/ecco-jcc/jjaa054. Online ahead of print

  25. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Wooland DL, Vignali DA. Lymphocyte activation gene 3(CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172:5450–5. https://doi.org/10.4049/jimmunol.172.9.5450.

    Article CAS Google Scholar

  26. Del Porto F, Cifani N, Proietta M, et al. (2019) Lag3+ regulatory T lymphocytes in critical carotid artery stenosis. Clin Exp Med. 2019;19:463–8. https://doi.org/10.1007/s10238-019-00570-x.

    Article CAS Google Scholar

  27. Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–13. https://doi.org/10.1016/j.immuni.2004.08.010.

    Article CAS Google Scholar

  28. Albert BB, de Bock M, Derraik JG, Brennan CM, Biggs JB, Hofman PL, Cutfield WS. Non-dipping and cardiometabolic profile: a study on normotensive overweight middle-aged men. Heart Lung Circ. 2016;25(12):1218–25. https://doi.org/10.1016/j.hlc.2016.04.012.

    Article Google Scholar

  29. Tanrıverdi O, Aşkın L, Serçelik A. Association between non-dipping status and carotid intima-media thickness in patients with elevated blood pressure category. Cardiovasc Surg Int. 2020;7(2):76–83. https://doi.org/10.5606/e-cvsi.2020.845.

    Article Google Scholar

  30. Kim JY, Lee E, Koo S, Kim CW, Kim I. Transfer of Th17 from adult spontaneous hypertensive rats accelerates development of hypertension in juvenile spontaneous hypertensive rats. Biomed Res Int. 2021:;2021: 6633825. https://doi.org/10.1155/2021/6633825. PMID: 33688497; PMCID: PMC791409.

    Article CAS Google Scholar

  31. Delaney JAC, Olson NC, Sitlani CM, et al. Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA). BMC Cardiovasc Disord. 2021;21:45. https://doi.org/10.1186/s12872-021-01857-2.

    Article CAS Google Scholar

  32. Mikolajczyk TP, Guzik TJ. Adaptative immunity and hypertension. Current Hypertens Rep. 2019;21:68. https://doi.org/10.1007/s11906-019-0971-6.

    Article CAS Google Scholar

  33. Albany CJ, Trevelin SC, Giganti G, Lombardi G, Scottà C. Getting to the hearth of the matter: the role of regulatory T cells (Tregs) in cardiovascular disease (CVD) and atherosclerosis. Frontier Immunol. 2019;10: 2795. https://doi.org/10.3389/fimmu.2019.02795.

    Article CAS Google Scholar

  34. Del Porto F, Cifani N, Proietta M, Toni D, Taurino M. MMP-12 and TIMP behaviour in symptomatic and asymptomatic critical carotid artery stenosis. J Stroke Cerebrovasc Dis. 2017;26:334–8. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.09.025. Epub 2016 Oct 13.

    Article Google Scholar

Funding

This work was founded by the Sapienza Università di Roma as “Progetto di Ricerca Universitaria” prot no. RM11916B5107B7E8.

Author information

Authors and Affiliations

  1. Dipartimento di Medicina Clinica e Molecolare, Facoltà di Medicina e Psicologia, Università degli Studi di Roma “La Sapienza”; UOC Medicina Interna, Azienda Ospedaliero-Universitaria Sant’Andrea, Rome, Italy

    Flavia Del Porto, Noemi Cifani, Maria Proietta, Antonio Martocchia & Giorgio Sesti

  2. Dipartimento di Medicina Clinica e Molecolare, Facoltà di Medicina e Psicologia, Università degli Studi di Roma “La Sapienza”; UOC Chirurgia Vascolare, Azienda Ospedaliero-Universitaria Sant’Andrea, Rome, Italy

    Pasqualino Sirignano & Maurizio Taurino

Contributions

Flavia Del Porto, Noemi Cifani Maurizio Taurino Giorgio Sesti and Maria Proietta. conceived the work, planned the experiments, and supervised the findings of this work Pasqualino Sirignano, Antonio Martocchia, Maurizio Taurino, Giorgio Sesti and Maria Proietta selected patients and performed laboratory and instrumental tests. Noemi Cifani and Flavia Del Porto carried out the experiments. All authors discussed the results and contributed to the final manuscript.All the Authors approved the version to be published.

Corresponding author

Correspondence to Flavia Del Porto.

Ethics declarations

Ethics Approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. The study was approved by the Local Ethics Committee of “Sapienza” University of Rome – Policlinico Umberto I Hospital and Sant’Andrea Hospital (project identification code 384/17). All enrolled patients provided informed written consent to be included in the present analysis.

Consent to Participate

Informed consent was obtained from all patients for inclusion in the study.

Written Consent for Publication

All enrolled patients provided informed written consent for the publication.

Competing interests

Flavia del Porto is Section Editor and Antonio Martocchia is Section Head forfor SN Comprehensive Clinical Medicine. They have not taken part in the review or selection process of this article. The authors declare no competing interests.

Additional information

About this article

Cite this article

Del Porto, F., Cifani, N., Proietta, M. et al. Regulatory T Lymphocyte Subpopulations in the Early Stages of Carotid Artery Stenosis. SN Compr. Clin. Med. 7, 215 (2025). https://doi.org/10.1007/s42399-025-01973-6

  • Received
  • Revised
  • Accepted
  • Published
  • DOI https://doi.org/10.1007/s42399-025-01973-6

Keyword

  • Carotid artery disease
  • Lymphocyte subpopulations
  • Regulatory T lymphocytes
  • Arterial hypertension

Copyright © All rights reserved Designed and Developed by Digital Flavers

WhatsApp