Treg Cells in Ischemic Stroke: A Small Key to a Great Orchestrion

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Abstract

Ischemic stroke is a global medical problem and one of the leading causes of death or disability worldwide. The main approach of ischemic stroke therapy in the most acute period, which can prevent or minimize the development of a neurological deficit, is the restoration of the blood flow in the ischemic brain tissue using enzymatic thrombolysis or endovascular thromboextraction. When the therapeutic window is missed, the modulation of the acute inflammatory response may play an important role in determining the fate of neurons in the penumbra. The key players in this process are T-regulatory cells (Tregs) — an immunosuppressive population of CD4+ T-cells with the CD4+, CD25+ CD127low, FoxP3+ phenotype. Despite the existing reports that Tregs (or certain Treg subpopulations) can exacerbate microcirculatory disorders in the ischemic tissue, many stadies convincingly suggest the positive role of Tregs in ischemic stroke. Resident CD69+ Tregs found in the normal mammalian brain have neuroprotective activity, produce IL-10 and other anti-inflammatory cytokines, control astrogliosis, and downregulate cytotoxic subpopulations of T cells and microglia. Systemic administration of Treg in stroke is accompained by a decrease in the volume of cerebral infarction and decreased levels of secondary neuronal death. Thus, the methods allowing Treg activation and expansion ex vivo open up several new avenues for the immunocorrection not only in systemic and autoimmune diseases, but, potentially, in the neuroprotective therapy for ischemic stroke. The relationship between Treg, inflammation, and cerebrovascular pathology is of particular interest in the case of ischemic stroke and COVID-19 as a comorbidity. It has been demonstrated that systemic inflammation caused by SARS-CoV-2 infection leads to a significant suppression of Treg, which is accompanied by an increased risk for the development of ischemic stroke and other neurological complications. Overall, the information summarized herein about the possible therapeutic potential of Treg in cerebrovascular pathology may be of practical interest not only for researchers, but also for clinicians.

About the authors

Oksana A. Zhukova

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency

Author for correspondence.
Email: Oksana.saprikina82@mail.ru
ORCID iD: 0000-0002-0907-0078

Research Associate

Russian Federation, Moscow

Daria A. Chudakova

Federal Center of Brain Research and Neurotechnologies

Email: daria.chudakova.bio@yandex.ru
ORCID iD: 0000-0002-9354-6824
SPIN-code: 1410-9581

PhD, Senior Researcher

Russian Federation, Moscow

Vladimir V. Belopasov

Astrakhan State Medical University

Email: belopasov@yandex.ru
ORCID iD: 0000-0003-0458-0703
SPIN-code: 6098-1321

MD, PhD, Dr. Sci. (Med.), Professor

Russian Federation, Astrakhan

Еlena V. Shirshova

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency

Email: shirshova.ev@fnkc-fmba.ru
ORCID iD: 0000-0002-3557-5424
SPIN-code: 7491-0434

MD, PhD, Dr. Sci. (Med.), Professor

Russian Federation, Moscow

Vladimir P. Baklaushev

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency; Federal Center of Brain Research and Neurotechnologies; Pulmonology Scientific Research Institute under Federal Medical and Biological Agency of Russsian Federation

Email: baklaushev.vp@fnkc-fmba.ru
ORCID iD: 0000-0003-1039-4245
SPIN-code: 3968-2971

MD, PhD, Dr. Sci. (Med.), Assistant Professor

Russian Federation, Moscow; Moscow; Moscow

Gaukhar M. Yusubalieva

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency; Federal Center of Brain Research and Neurotechnologies; Pulmonology Scientific Research Institute under Federal Medical and Biological Agency of Russsian Federation

Email: gaukhar@gaukhar.org
ORCID iD: 0000-0003-3056-4889
SPIN-code: 1559-5866

MD, PhD

Russian Federation, Moscow; Moscow; Moscow

References

  1. Feigin VL, Brainin M, Norrving B, et al. World Stroke Organization (WSO): Global stroke fact sheet 2022. Int J Stroke. 2022;17(1): 18–29. doi: 10.1177/17474930211065917
  2. Sakai S, Shichita T. Inflammation and neural repair after ischemic brain injury. Neurochem Int. 2019;(130):104316. doi: 10.1016/j.neuint.2018.10.013
  3. Федин А.И., Бадалян К.Р. Обзор клинических рекомендаций лечения и профилактики ишемического инсульта // Журнал неврологии и психиатрии им. С.С. Корсакова. 2019. Т. 119, № 8-2. С. 95–100. [Fedin AI, Badalyan KR. Review of clinical recommendations for the treatment and prevention of ischemic stroke. J Neurology Psychiatry named after S.S. Korsakov. 2019;119(8-2):95–100. (In Russ).] doi: 10.17116/jnevro201911908295
  4. Alim I, Caulfield JT, Chen Y, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. 2019;177(5):1262–1279. doi: 10.1016/j.cell.2019.03.032
  5. Zhang SR, Phan TG, Sobey CG. Targeting the immune system for ischemic stroke. Trends Pharmacol Sci. 2021;42(2):96–105. doi: 10.1016/j.tips.2020.11.010
  6. Воробьев С.В., Янишевский С.Н., Кудрявцев И.В., и др. Участие иммунного ответа в патогенезе ишемического инсульта // Медицинский совет. 2023. № 3. С. 8–16. [Vorobyev SV, Yanishevsky SN, Kudryavtsev IV, et al. Involvement of the immune response in the pathogenesis of ischemic stroke. Medical Advice. 2023;(3):8–16. (In Russ).]
  7. Thapa K, Shivam K, Khan H, et al. Emerging targets for modulation of immune response and inflammation in stroke. Neurochem Res. 2023;48(6):1663–1690. doi: 10.1007/s11064-023-03875-2
  8. Lifshitz GV, Zhdanov DD, Lokhonina AV, et al. Ex vivo expanded regulatory T cells CD4+CD25+FoxP3+CD127Low develop strong immunosuppressive activity in patients with remitting-relapsing multiple sclerosis. Autoimmunity. 2016;49(6):388–396. doi: 10.1080/08916934.2016.1199020
  9. Brea D, Agulla J, Rodríguez-Yáñez M, et al. Regulatory T cells modulate inflammation and reduce infarct volume in experimental brain ischaemia. J Cell Mol Med. 2014;18(8): 1571–1579. doi: 10.1111/jcmm.12304
  10. Olson KE, Mosley RL, Gendelman HE. The potential for Treg-enhancing therapies in nervous system pathologies. Clin Exp Immunol. 2023;211(2):108–121. doi: 10.1093/cei/uxac084
  11. 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(4):679–691. doi: 10.1182/blood-2012-04-426734
  12. Selvaraj UM, Stowe AM. Long-term T cell responses in the brain after an ischemic stroke. Discovery Med. 2017;24(134):323.
  13. Wu Y, Li J, Shou J, et al. Diverse functions and mechanisms of regulatory T cell in ischemic stroke. Exp Neurol. 2021; (343):113782. doi: 10.1016/j.expneurol.2021.113782
  14. Malviya V, Yshii L, Junius S, et al. Regulatory T‐cell stability and functional plasticity in health and disease. Immunol Cell Biol. 2023;101(2):112–129. doi: 10.1111/imcb.12613
  15. Mao L, Li P, Zhu W, et al. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain. 2017;140(7):1914–1931. doi: 10.1093/brain/awx111
  16. Yuan C, Shi L, Sun Z, et al. Regulatory T cell expansion promotes white matter repair after stroke. Neurobiol Dis. 2023;(179):106063. doi: 10.1016/j.nbd.2023.106063
  17. Sarvari S, Moakedi F, Hone E, et al. Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke. Metab Brain Dis. 2020;35(6):851–868. doi: 10.1007/s11011-020-00573-8
  18. Nikolic D, Jankovic M, Petrovic B, Novakovic I. Genetic aspects of inflammation and immune response in stroke. Int J Mol Sci. 2020;21(19):7409. doi: 10.3390/ijms21197409
  19. Rayasam A, Hsu M, Kijak JA, et al. Immune responses in stroke: How the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures? Immunology. 2018;154(3):363–376. doi: 10.1111/imm.12918
  20. Tobin MK, Bonds JA, Minshall RD, et al. Neurogenesis and inflammation after ischemic stroke: What is known and where we go from here. J Cereb Blood Flow Metab. 2014;34(10): 1573–1584. doi: 10.1038/jcbfm.2014.130
  21. Rustenhoven J, Drieu A, Mamuladze T, et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. 2021;184(4):1000–1016.e27. doi: 10.1016/j.cell.2020.12.040
  22. Fan X, Chen H, Jiang F, et al. Comprehensive analysis of cuproptosis-related genes in immune infiltration in ischemic stroke. Front Neurol. 2023;(13):1077178. doi: 10.3389/fneur.2022.1077178
  23. Tuo QZ, Zhang ST, Lei P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med Res Rev. 2022;(42):259–305. doi: 10.1002/med.21817
  24. Yang K, Zhang Z, Liu X, et al. Identification of hypoxia-related genes and exploration of their relationship with immune cells in ischemic stroke. Sci Rep. 2023;13(1):10570. doi: 10.1038/s41598-023-37753-2
  25. Mao R, Zong N, Hu Y, et al. Neuronal death mechanisms and therapeutic strategy in ischemic stroke. Neurosci Bull. 2022;38(10):1229–1247. doi: 10.1007/s12264-022-00859-0
  26. Samoilova EM, Yusubalieva GM, Belopasov VV, et al. Infections and inflammation in the development of stroke. J Neurology Psychiatry named after S.S. Korsakov. 2021;121(8-2):11-21. (In Russ). doi: 10.17116/jnevro202112108211
  27. Han L, Wang Z, Yuan J, et al. Circulating leukocyte as an inflammatory biomarker: Association with fibrinogen and neuronal damage in acute ischemic stroke. J Inflamm Res. 2023;(16):1213–1226. doi: 10.2147/JIR.S399021
  28. Seifert HA, Vandenbark AA, Offner H. Regulatory B cells in experimental stroke. Immunology. 2018;154(2):169–177. doi: 10.1111/imm.12887
  29. Ito M, Komai K, Mise-Omata S, et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature. 2019;565(7738):246–250. doi: 10.1038/s41586-018-0824-5
  30. Astarita JL, Dominguez CX, Tan C, et al. Treg specialization and functions beyond immune suppression. Clin Exp Immunol. 2023;211(2):176–183. doi: 10.1093/cei/uxac123
  31. Wang Y, Sadike D, Huang B, et al. Regulatory T cells alleviate myelin loss and cognitive dysfunction by regulating neuroinflammation and microglial pyroptosis via TLR4/MyD88/NF-κB pathway in LPC-induced demyelination. J Neuroinflammation. 2023;20(1):41. doi: 10.1186/s12974-023-02721-0
  32. Bluestone JA, McKenzie BS, Beilke J, Ramsdell F. Opportunities for Treg cell therapy for the treatment of human disease. Front Immunol. 2023;(14):1166135. doi: 10.3389/fimmu.2023.1166135
  33. Li Y, McBride DW, Tang Y, et al. Immunotherapy as a treatment for stroke: Utilizing regulatory T cells. Brain Hemorrhages. 2023. doi: 10.1016/j.hest.2023.02.003
  34. Zhang Y, Liesz A, Li P. Coming to the rescue: Regulatory T cells for promoting recovery after ischemic stroke. Stroke. 2021;52(12):e837–e841. doi: 10.1161/STROKEAHA.121.036072
  35. Qiao C, Liu Z, Qie S. The Implications of microglial regulation in neuroplasticity-dependent stroke recovery. Biomolecules. 2023;13(3):571. doi: 10.3390/biom13030571
  36. Ruhnau J, Schulze J, von Sarnowski B, et al. Reduced numbers and impaired function of regulatory T cells in peripheral blood of ischemic stroke patients. Mediators Inflamm. 2016;2016:2974605. doi: 10.1155/2016/2974605
  37. Thornton AM, Lu J, Korty PE, et al. Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires. Eur J Immunol. 2019;49(3):398–412. doi: 10.1002/eji.201847935
  38. Thornton AM, Korty PE, Tran DQ, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic- derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010;184(7):3433–3441. doi: 10.4049/jimmunol.0904028
  39. Reinhardt J, Sharma V, Stavridou A, et al. Distinguishing activated T regulatory cell and T conventional cells by single-cell technologies. Immunology. 2022;166(1):121–137. doi: 10.1111/imm.13460
  40. Mishra S, Srinivasan S, Ma C, Zhang N. CD8+ regulatory T cell: A mystery to be revealed. Front Immunol. 2021;(12):708874. doi: 10.3389/fimmu.2021.708874
  41. Zhang B, Zhang X, Tang FL, et al. Clinical significance of increased CD4+ CD25- Foxp3+ T cells in patients with new-onset systemic lupus erythematosus. Ann Rheum Dis. 2008;67(7):1037–1040. doi: 10.1136/ard.2007.083543
  42. Liston A, Dooley J, Yshii L. Brain-resident regulatory T cells and their role in health and disease. Immunol Letters. 2022;(248): 26–30. doi: 10.1016/j.imlet.2022.06.005
  43. Khantakova JN, Bulygin AS, Sennikov SV. The regulatory T-cell memory phenotype: What we know. Cells. 2022;11(10):1687. doi: 10.3390/cells11101687
  44. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nature Immunol. 2003;4(4):330–336. doi: 10.1038/ni904
  45. Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445(7129):766–770. doi: 10.1038/nature05479
  46. Husebye ES, Anderson MS, Kämpe O. Autoimmune polyendocrine syndromes. N Engl J Med. 2018;378(12):1132–1141. doi: 10.1056/NEJMra1713301
  47. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–1061. doi: 10.1126/science.1079490
  48. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157–167. doi: 10.1038/nri3155
  49. Allan SE, Passerini L, Bacchetta R., et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest. 2005;115(11):3276–3284. doi: 10.1172/JCI24685
  50. Mailer RK, Falk K, Rotzschke O. Absence of leucine zipper in the natural FOXP3D2D7 isoform does not affect dimerization but abrogates suppressive capacity. PLoS One. 2009;4(7):e6104. doi: 10.1371/journal.pone.0006104
  51. Донецкова А.Д., Литвина М.М., Смирнов Д.С., и др. Сравнение экспрессии изоформ молекулы FOXP3 регуляторными Т-клетками периферической крови при аллергических и лимфопролиферативных заболеваниях // Русский медицинский журнал. 2020. Т. 4, № 1. С. 4–9. [Donetskova AD, Litvina MM, Smirnov DS, et al. Comparison of the expression of isoforms of the FOXP3 molecule by regulatory T cells of peripheral blood in allergic and lymphoproliferative diseases. Russ Med J. 2020;4(1):4–9. (In Russ).]
  52. Bushnell CD, Chaturvedi S, Gage KR, et al. Sex differences in stroke: Challenges and opportunities. J Cereb Blood Flow Metab. 2018;38(12):2179–2191. doi: 10.1177/0271678X18793324
  53. Arruvito L, Sanz M, Banham AH, Fainboim L. Expansion of CD4+CD25+ and FOXP3+ Regulatory T cells during the follicular phase of the menstrual cycle: Implications for human reproduction. J Immunol. 2014;178(4):2572–2578. doi: 10.4049/jimmunol.178.4.2572
  54. Lee JH, Lydon JP, Kim CH. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur J Immunol. 2012;(42):2683–2696. doi: 10.1002/eji.201142317
  55. Brown MA, Su MA. An inconvenient variable: Sex hormones and their impact on T cell responses. J Immunol. 2019;202(7): 1927–1933. doi: 10.4049/jimmunol.1801403
  56. McCullough LD, Mirza MA, Xu Y, et al. Stroke sensitivity in the aged: Sex chromosome complement vs. gonadal hormones. Aging (Albany NY). 2016;8(7):1432. doi: 10.18632/aging.100997
  57. Savage PA, Klawon DE, Miller CH. Regulatory T cell development. Annu Rev Immunol. 2020;(38):421–453. doi: 10.1146/annurev-immunol-100219-020937
  58. De Lafaille MA, Lafaille JJ. Natural and adaptive FOXP3+ regulatory T cells: More of the same or a division of labor? Immunity. 2009;30(5):626–635. doi: 10.1016/j.immuni.2009.05.002
  59. Lal G, Zhang N, van der Touw W, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259–273. doi: 10.4049/jimmunol.182.1.259
  60. Magg T, Mannert J, Ellwart JW, et al. Subcellular localization of FOXP3 in human regulatory and nonregulatory T cells. Eur J Immunol. 2012;42(6):1627–1638. doi: 10.1002/eji.201141838
  61. Yang W, Yu T, Cong Y. CD4+ T cell metabolism, gut microbiota, and autoimmune diseases: Implication in precision medicine of autoimmune diseases. Precis Clin Med. 2022;5(3):pbac018. doi: 10.1093/pcmedi/pbac018
  62. Angelin A, Gil-de-Gómez L, Dahiya S, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metabol. 201725(6):1282–1293.e7. doi: 10.1016/j.cmet.2016.12.018
  63. André S, Tough DF, Lacroix-Desmazes S, et al. Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: Immunopathogenesis and therapeutic implications. Am J Pathol. 2009;174(5):1575–1587. doi: 10.2353/ajpath.2009.080987
  64. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899): 271–275. doi: 10.1126/science.1160062
  65. Qiu M, Zong JB, He QW, et al. Cell heterogeneity uncovered by single-cell RNA sequencing offers potential therapeutic targets for ischemic stroke. Aging Dis. 2022;13(5):1436–1454. doi: 10.14336/AD.2022.0212
  66. Miragaia RJ, Gomes T, Chomka A, et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity. 2019;50(2):493–504.e7. doi: 10.1016/j.immuni.2019.01.001
  67. Szabo PA, Levitin HM, Miron M, et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat Commun. 2019;10(1):4706. doi: 10.1038/s41467-019-12464-3
  68. Dolati S, Ahmadi M, Khalili M, et al. Peripheral Th17/Treg imbalance in elderly patients with ischemic stroke. Neurol Sci. 2018;39(4):647–654. doi: 10.1007/s10072-018-3250-4
  69. Santamaría-Cadavid M, Rodríguez-Castro E, Rodríguez-Yáñez M, et al. Regulatory T cells participate in the recovery of ischemic stroke patients. BMC Neurol. 2020;20(1):68. doi: 10.1186/s12883-020-01648-w
  70. Chan A, Yan J, Csurhes P, et al. Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: Effect on outcome. J Neuroimmunol. 2015;(286):42–47. doi: 10.1016/j.jneuroim.2015.06.013
  71. Pang X, Qian W. Changes in regulatory T-cell levels in acute cerebral ischemia. J Neurol Surg A Cent Eur Neurosurg. 2017;78(4):374–379. doi: 10.1055/s-0037-1599055
  72. Booth NJ, McQuaid AJ, Sobande T, et al. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol. 2010;184(8):4317–4326. doi: 10.4049/jimmunol.0903781
  73. Deng G, Tang Y, Xiao J, et al. Naïve-memory regulatory T cells ratio is a prognostic biomarker for patients with acute ischemic stroke. Front Aging Neurosci. 2023;(15):1072980. doi: 10.3389/fnagi.2023.1072980
  74. Li S, Huang Y, Liu Y, et al. Change and predictive ability of circulating immunoregulatory lymphocytes in long-term outcomes of acute ischemic stroke. J Cereb Blood Flow Metab. 2021;41(9):2280–2294. doi: 10.1177/0271678X21995694
  75. Yan J, Greer JM, Etherington K, et al. Immune activation in the peripheral blood of patients with acute ischemic stroke. J Neuroimmunol. 2009;206(1-2):112–117. doi: 10.1016/j.jneuroim.2008.11.001
  76. Wang M, Thomson AW, Yu F, et al. Regulatory T lymphocytes as a therapy for ischemic stroke. Semin Immunopathol. 2023;45(3):329–346. doi: 10.1007/s00281-022-00975-z
  77. Xiao S, Jin H, Korn T, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol. 2008;181(4): 2277–2284. doi: 10.4049/jimmunol.181.4.2277
  78. Manicassamy S, Pulendran B. Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages. Seminars Immunol. 2009;21(1):22–27. doi: 10.1016/j.smim.2008.07.007
  79. Патент РФ № RU 2791738 C1. Шардина К.Ю., Заморина С.А., Бочкова М.С., и др. Способ получения аутологичных регуляторных Т-лимфоцитов путем культивирования ex vivo в присутствии хорионического гонадотропина. [Patent RUS RU 2791738 C1. Shardina KYu, Zamorina SA, Bochkova MS, et al. A method for obtaining autologous regulatory T-lymphocytes by culturing ex vivo in the presence of chorionic gonadotropin. (In Russ).] Режим доступа: https://patents.google.com/patent/RU2791738C1/ru. Дата обращения: 15.08.2023.
  80. Golovina TN, Mikheeva T, Brusko TM, et al. Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells. PloS One. 2011;6(1):e15868. doi: 10.1371/journal.pone.0015868
  81. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+regulatory T cells. Blood. 2005; 105(12):4743–4748. doi: 10.1182/blood-2004-10-3932
  82. Chapman NM, Zeng H, Nguyen TL, et al. mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat Commun. 2018;9(1):2095. doi: 10.1038/s41467-018-04392-5
  83. Chan MW, Chang CB, Tung CH, et al. Low-dose 5-aza-2'-deoxycytidine pretreatment inhibits experimental autoimmune encephalomyelitis by induction of regulatory T cells. Mol Med. 2014;20(1):248–256. doi: 10.2119/molmed.2013.00159
  84. Polansky JK, Kretschmer K, Freyer J, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008; 38(6):1654–1663. doi: 10.1002/eji.200838105
  85. Zhang H, Xia Y, Ye Q, et al. In vivo expansion of regulatory T cells with IL-2/IL-2 antibody complex protects against transient ischemic stroke. J Neurosci. 2018;38(47):10168–10179. doi: 10.1523/JNEUROSCI.3411-17.2018
  86. Greilach SA, McIntyre LL, Nguyen QH, et al. Presentation of human neural stem cell antigens drives regulatory T cell induction. J Immunol. 2023;210(11):1677–1686. doi: 10.4049/jimmunol.2200798
  87. Xia Y, Hu G, Chen Y, et al. Embryonic stem cell derived small extracellular vesicles modulate regulatory T cells to protect against ischemic stroke. ACS Nano. 2021;15(4):7370–7385. doi: 10.1021/acsnano.1c00672
  88. Guo S, Luo Y. Brain Foxp3+ regulatory T cells can be expanded by Interleukin-33 in mouse ischemic stroke. Int Immunopharmacol. 2020;(81):106027. doi: 10.1016/j.intimp.2019
  89. Shu L, Xu C, Yan ZY, et al. Post-Stroke microglia induce Sirtuin2 expression to suppress the anti-inflammatory function of infiltrating regulatory T cells. Inflammation. 2019;42(6): 1968–1979. doi: 10.1007/s10753-019-01057-3
  90. Pan Z, Ma G, Kong L, Du G. Hypoxia-inducible factor-1: Regulatory mechanisms and drug development in stroke. Pharmacol Res. 2021;(170):105742. doi: 10.1016/j.phrs.2021.105742
  91. Yu HH, Ma XT, Ma X, et al. Remote limb ischemic postconditioning protects against ischemic stroke by promoting regulatory T cells thriving. J Am Heart Assoc. 2021;10(22):e023077. doi: 10.1161/JAHA.121.023077
  92. Zhang Y, Liesz A, Li P. Coming to the rescue: Regulatory T cells for promoting recovery after ischemic stroke. Stroke. 2021;52(12):e837–e841. doi: 10.1161/STROKEAHA.121.036072
  93. Liu C, Li N, Liu G. The role of MicroRNAs in regulatory T cells. J Immunol Res. 2020;2020:3232061. doi: 10.1155/2020/3232061
  94. Kadir RR, Alwjwaj M, Bayraktutan U. MicroRNA: An emerging predictive, diagnostic, prognostic and therapeutic strategy in ischaemic stroke. Cell Mol Neurobiol. 2022;42(5):1301–1319. doi: 10.1007/s10571-020-01028-5
  95. Xu W, Gao L, Zheng J, et al. The roles of MicroRNAs in stroke: Possible therapeutic targets. Cell Transplant. 2018;27(12): 1778–1788. doi: 10.1177/0963689718773361
  96. Copsel SN, Malek TR, Levy RB. Medical treatment can unintentionally alter the regulatory T cell compartment in patients with widespread pathophysiologic conditions. Am J Pathol. 2020;190(10):2000–2012. doi: 10.1016/j.ajpath.2020.07.012
  97. Полуэктов М.Г., Нарбут А.М., Шувахина Н.А. Применение мелатонина в качестве нейропротектора при ишемическом инсульте // Медицинский совет. 2019. № 18. С. 18–24. [Poluektov MG, Narbut AM, Shuvakhina NA. The use of melatonin as a neuroprotector in ischemic stroke. Medical Council. 2019;(18):18–24. (In Russ).]
  98. Ren W, Liu G, Chen S, et al. Melatonin signaling in T cells: Functions and applications. J Pineal Res. 2017;62(3):e12394. doi: 10.1111/jpi.12394
  99. Medrano‐Campillo P, Sarmiento‐Soto H, Álvarez‐Sánchez N, et al. Evaluation of the immunomodulatory effect of melatonin on the T‐cell response in peripheral blood from systemic lupus erythematosus patients. J Pineal Res. 2015;58(2):219–226. doi: 10.1111/jpi.12208
  100. Sharma S, Nozohouri S, Vaidya B, Abbruscato T. Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke. Life Sci. 2021;(274):119343. doi: 10.1016/j.lfs.2021.119343
  101. Lee SK, Park MJ, Jhun JY, et al. Combination treatment with metformin and tacrolimus improves systemic immune cellular homeostasis by modulating Treg and Th17 imbalance. Front Immunol. 2021;(11):581728. doi: 10.3389/fimmu.2020.581728
  102. Wang Z, Kawabori M, Houkin K. FTY720 (Fingolimod) ameliorates brain injury through multiple mechanisms and is a strong candidate for stroke treatment. Curr Med Chem. 2020; 27(18):2979–2993. doi: 10.2174/0929867326666190308133732
  103. Malone K, Diaz Diaz AC, Shearer JA, et al. The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia. J Neuroinflammation. 2021;18(1):37. doi: 10.1186/s12974-021-02083-5
  104. Noh MY, Lee WM, Lee SJ, et al. Regulatory T cells increase after treatment with poly (ADP-ribose) polymerase-1 inhibitor in ischemic stroke patients. Int Immunopharmacol. 2018;(60): 104–110. doi: 10.1016/j.intimp.2018.04.043
  105. Luo X, Nie J, Wang S, et al. Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J Biol Chem. 2015;290(48):28675–82. doi: 10.1074/jbc.M115.661611
  106. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504(7480):451–455. doi: 10.1038/nature12726
  107. Akimova T, Ge G, Golovina T, et al. Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. Clin Immunol. 2010;136(3):348–363. doi: 10.1016/j.clim.2010.04.018
  108. Ao LY, Yan YY, Zhou L, et al. Immune cells after ischemic stroke onset: Roles, migration, and target intervention. J Mol Neurosci. 2018;66(3):342–355. doi: 10.1007/s12031-018-1173-4
  109. Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab. 2014;34(2):185–199. doi: 10.1038/jcbfm.2013.203
  110. Pinheiro MA, Kooij G, Mizee MR, et al. Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim Biophys Acta. 2016;1862(3): 461–471. doi: 10.1016/j.bbadis.2015.10.018
  111. Zhang D, Ren J, Luo Y, et al. T cell response in ischemic stroke: From mechanisms to translational insights. Front Immunol. 2021;(12):707972. doi: 10.3389/fimmu.2021.707972
  112. 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(1):37–47. doi: 10.1038/jcbfm.2012.128
  113. Yu H, Cai Y, Zhong A, et al. The «dialogue» between central and peripheral immunity after ischemic stroke: Focus on spleen. Front Immunol. 2021;(12):5194. doi: 10.3389/fimmu.2021.792522
  114. Белопасов В.В., Журавлева Е.Н., Нугманова Н.П., Абдрашитова А.Т. Постковидные неврологические синдромы // Клиническая практика. 2021. Т. 12, № 2. C. 69–82. [Belopasov VV, Zhuravleva EN, Nugmanova NP, Abdrashitova AT. Postcovid neurological syndromes. Clin Pract. 2021;12(2):69–82. (In Russ).] doi: 10.17816/clinpract71137
  115. Ahmad SJ, Feigen CM, Vazquez JP, et al. Neurological Sequelae of COVID-19. J Integr Neurosci. 2022;21(3):77. doi: 10.31083/j.jin2103077
  116. Belopasov VV, Yachou Y, Samoilova EM, Baklaushev VP. The nervous system damage in COVID-19. J Clin Pract. 2020. Vol. 11, N 2. P. 60–80. doi: 10.17816/clinpract34851
  117. Katsanos AH, Palaiodimou L, Zand R, et al. The impact of SARS-CoV-2 on stroke epidemiology and care: A meta-analysis. Ann Neurol. 2021;89:380–388. doi: 10.1002/ana.25967
  118. Sadeghi A, Tahmasebi S, Mahmood A, et al. Th17 and Treg cells function in SARS‐CoV-2 patients compared with healthy controls. J Cell Physiol. 2021;236(4):2829–2839. doi: 10.1002/jcp.30047
  119. Wang H, Wang Z, Cao W, et al. Regulatory T cells in COVID-19. Aging Dis. 2021;12(7):1545–1553. doi: 10.14336/AD.2021.0709
  120. Wang HY, Ye JR, Cui LY, et al. Regulatory T cells in ischemic stroke. Acta Pharmacol Sin. 2022;43(1):1–9. doi: 10.1038/s41401-021-00641-4
  121. Dhawan M, Rabaan AA, Alwarthan S, et al. Regulatory T Cells (Tregs) and COVID-19: Unveiling the mechanisms, and therapeutic potentialities with a special focus on long COVID. Vaccines (Basel). 2023;11(3):699. doi: 10.3390/vaccines11030699
  122. Haunhorst S, Bloch W, Javelle F, et al. A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients: Indications for their potential involvement in the development of Long COVID? Front Immunol. 2022;(13):1070994. doi: 10.3389/fimmu.2022
  123. Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19. Cell. 2020;183(5):1340–1353.e16. doi: 10.1016/j.cell.2020.10.001
  124. Hoffmann AD, Weinberg SE, Swaminathan S, et al. Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients. Clin Immunol. 2023;(252):109634. doi: 10.1016/j.clim.2023.109634
  125. Rizzo PA, Bellavia S, Scala I, et al. COVID-19 vaccination is associated with a better outcome in acute ischemic stroke patients: A retrospective observational study. J Clin Med. 2022;11(23):6878. doi: 10.3390/jcm11236878

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