CHANGES IN THE SUBPOPULATION COMPOSITION AND PHENOTYPES OF T-LYMPHOCYTES AND B-LYMPHOCYTES DURING THE USE OF RECOMBINANT INTERLEUKIN-2 IN PATIENTS WITH POST-COVID SYNDROME



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Abstract

Post-COVID syndrome (PCS) is characterized by symptoms of varying etiology and severity, which is largely associated with its multifactorial etiology and the development of local and systemic chronic inflammation. T lymphocytes, B lymphocytes, and NKT cells are key cells of adaptive immunity that play an important role in the regulation and maintenance of inflammatory processes, determining the direction of the immune response. The features of their subpopulation composition and phenotypes remain insufficiently studied, which hinders the understanding of the mechanisms underlying this condition and, consequently, the development of effective rehabilitation methods.
Aim of the study – to evaluate the effect of recombinant interleukin-2 (IL-2) on the subpopulation composition and phenotypic characteristics of lymphocytes in patients with post-COVID syndrome.
Materials and Methods. The observational prospective study included 29 patients (40–65 years) with post-COVID syndrome who received recombinant IL-2 (0,5 mg subcutaneously three times at 48-hour intervals) in addition to baseline therapy. Immunological parameters were assessed by flow cytometry before and after treatment. The control group consisted of 30 healthy volunteers matched for sex and age.
Results. At baseline, patients with post-COVID syndrome showed a statistically significant decrease in total B-cell counts, CD19⁺CD5⁻CD23⁺ and CD19⁺CD27⁺ subpopulations, an increase in activated T-helper cells (CD38⁺CD39⁺, CD39⁺CD73⁺), an increased proportion of memory cells and activated T-regulatory cells with a concomitant decrease in effector populations, as well as a reduction in cytotoxic T-lymphocytes and NKT cells. After IL-2 therapy, an increase in NKT-cell counts was observed, especially their mature subpopulations (CD94⁺CD57⁺), along with a rise in activated (CD25⁺) T-helper cells and T-regulatory cells.
Conclusion. The use of recombinant IL-2 in patients with post-COVID syndrome is accompanied by a significant restructuring of the immune response with activation of the T-cell response and regulatory compartment, as well as partial restoration of the functional activity of the NKT-cell component. The data obtained demonstrate that IL-2-induced correction of the lymphocyte subpopulation composition, including an increase in terminally differentiated CD94⁺CD57⁺ NKT cells, contributes to the enhancement of the immune response and the control of chronic inflammation.

About the authors

Ivan S. Sadowski

Scientific and Research Institute of Medical Problems of the North of the Federal Research Centre "Krasnoyarsk Scientific Centre of the Siberian Branch of the Russian Academy of Science", Krasnoyarsk, Russian Federation

Email: sadovskii24@rambler.ru
ORCID iD: 0000-0003-0338-4647
SPIN-code: 3624-9788

Postgraduate student, Junior Researcher at the Laboratory of Cellular and Molecular Physiology and Pathology, of the Federal State Budgetary Scientific Institution "Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences'", Separate Subdivision "Research Institute of Medical Problems of the North", Krasnoyarsk, Russian Federation

Russian Federation, 660022, Krasnoyarsk, P.Zheleznyaka Str., 3 g.

Anton S. Mikhalev

Federal State Autonomous Educational Institution of Higher Education "Siberian Federal University", Institute of Space and Information Technologies

Email: asmikhalev@yandex.ru
ORCID iD: 0000-0002-8986-5953
SPIN-code: 7980-2691

Senior Lecturer at the Institute of Space and Information Technologies

Russian Federation, 660074, Krasnoyarsk, ul. Akademika Kirenskogo, 26B

Andrei A. Savchenko

Scientific and Research Institute of Medical Problems of the North of the Federal Research Centre "Krasnoyarsk Scientific Centre of the Siberian Branch of the Russian Academy of Science", Krasnoyarsk, Russian Federation

Email: aasavchenko@yandex.ru
ORCID iD: 0000-0001-5829-672X
SPIN-code: 3132-8260

PhD, MD (Medicine), Professor, Head, Laboratory of Cellular and Molecular Physiology and Pathology, Research Institute of Medical Problems of the North, Federal Research Center, Siberian Branch, Russian Academy of Sciences

Russian Federation, Krasnoyarsk

Elena N. Anisimova

Scientific and Research Institute of Medical Problems of the North of the Federal Research Centre "Krasnoyarsk Scientific Centre of the Siberian Branch of the Russian Academy of Science", Krasnoyarsk, Russian Federation

Email: foi-543@mail.ru
ORCID iD: 0000-0002-6120-159X
SPIN-code: 4610-7610

PhD in Medicine, Senior Research Fellow at the Laboratory of Cellular and Molecular Physiology and Pathology

Russian Federation, 660022, Krasnoyarsk, Partizana Zheleznyaka St., 3G

Sergey A. Borisov

Krasnoyarsk State Budgetary Healthcare Institution Krasnoyarsk Interdistrict Clinical Hospital No. 20 named after I.S. Berzona, Krasnoyarsk, Russia

Email: borisov1207@mail.ru
ORCID iD: 0000-0002-0449-5333

Deputy Chief Physician for Surgery, Krasnoyarsk Interdistrict Clinical Hospital No. 20 named after I.S. Berzon, Krasnoyarsk, Russian Federation

Russian Federation, 660123, Krasnoyarsk, Instrumentalnaya St., 12

Alexandr G. Borisov

Scientific and Research Institute of Medical Problems of the North of the Federal Research Centre "Krasnoyarsk Scientific Centre of the Siberian Branch of the Russian Academy of Science", Krasnoyarsk, Russian Federation

Author for correspondence.
Email: 2885263@mail.ru
ORCID iD: 0000-0002-9026-2615
SPIN-code: 9570-2254

PhD Medicine, Leading Research Associate, Laboratory of Cellular and Molecular Physiology and Pathology, Research Institute of Medical Problems of the North, Federal Research Center, Siberian Branch, Russian Academy of Sciences

Russian Federation, Krasnoyarsk

References

  1. Акинфиева О.В., Бубнова Л.Н., Бессмельцев С.С. NKT-клетки: характерные свойства и функциональная значимость для регуляции иммунного ответа // Онкогематология. – 2010. – № 4. – С. 39–47. AKINFIEVA O.V., BUBNOVA L.N., BESSMELTSEV S.S. NKT CELLS: CHARACTERISTIC PROPERTIES AND FUNCTIONAL SIGNIFICANCE FOR IMMUNE RESPONSE REGULATION. ONCOHEMATOLOGY, 2010, NO. 4, PP. 39–47.
  2. Асфандиярова Н.С., Филиппов Е.В., Демихов В.Г., Дашкевич О.В., Якубовская А.Г., Мосейчук К.А., Журавлева Н.С., Куликов С.А. Клинические проявления постковидного синдрома // РМЖ. Медицинское обозрение. – 2022. – Т. 6, № 11. – С. 612–617. ASFANDIYAROVA N.S., FILIPPOV E.V., DEMIKHOV V.G., DASHKEVICH O.V., YAKUBOVSKAYA A.G., MOSEYCHUK K.A., ZHURAVLEVA N.S., KULIKOV S.A. CLINICAL MANIFESTATIONS OF POST-COVID SYNDROME. RMJ. MEDICAL REVIEW, 2022, VOL. 6, NO. 11, PP. 612–617 https://doi.org/10.32364/2587-6821-2022-6-11-612-617
  3. [doi: 10.32364/2587-6821-2022-6-11-612-617]
  4. Alijotas-Reig J, Anunciacion-Llunell A, Esteve-Valverde E, Morales-Pérez S, Rivero-Santana S, Trapé J, González-García L, Ruiz D, Marques-Soares J, Miro-Mur F. Pituitary-Adrenal Axis and Peripheral Immune Cell Profile in Long COVID. Biomedicines. 2024 Mar 5;12(3):581. https://doi.org/10.3390/biomedicines12030581
  5. [doi: 10.3390/biomedicines12030581]
  6. Berger L, Wolf J, Kalbitz S, Kellner N, Lübbert C, Borte S. Comparative Analysis of Lymphocyte Populations in Post-COVID-19 Condition and COVID-19 Convalescent Individuals. Diagnostics (Basel). 2024 Jun 18;14(12):1286. https://doi.org/10.3390/diagnostics14121286
  7. [doi: 10.3390/diagnostics14121286]
  8. Dorneles GP, Teixeira PC, da Silva IM, Schipper LL, Santana Filho PC, Rodrigues Junior LC, Bonorino C, Peres A, Fonseca SG, Monteiro MC, Boeck CR, Eller S, Oliveira TF, Wendland EM, Romão PRT. Alterations in CD39/CD73 axis of T cells associated with COVID-19 severity. J Cell Physiol. 2022 Aug;237(8):3394-3407. https://doi.org/10.1002/jcp.30805
  9. [doi: 10.1002/jcp.30805]
  10. Graßhoff H., Comdühr S., Monne L.R., Müller A., Lamprecht P., Riemekasten G., Humrich J.Y. Low-Dose IL-2 Therapy in Autoimmune and Rheumatic Diseases. Frontiers in Immunology. 2021;12:648408. https://doi.org/10.3389/fimmu.2021.648408
  11. [doi: 10.3389/fimmu.2021.648408]
  12. He J., Zhang X., Wei Y. et al. Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nature Medicine. 2016;22(9):991–993. https://doi.org/10.1038/nm.4148
  13. [doi: 10.1038/nm.4148]
  14. Herrera L, Martin-Inaraja M, Santos S, Inglés-Ferrándiz M, Azkarate A, Perez-Vaquero MA, Vesga MA, Vicario JL, Soria B, Solano C, De Paz R, Marcos A, Ferreras C, Perez-Martinez A, Eguizabal C. Identifying SARS-CoV-2 'memory' NK cells from COVID-19 convalescent donors for adoptive cell therapy. Immunology. 2022 Feb;165(2):234-249. https://doi.org/10.1111/imm.13433
  15. [doi: 10.1111/imm.13433]
  16. Klok F.A., Boon G.J.A.M., Barco S., Endres M., Geelhoed J.J.M., Knauss S., Rezek S.A., Spruit M.A., Vehreschild J., Siegerink B. The Post-COVID-19 Functional Status scale: a tool to measure functional status over time after COVID-19. European Respiratory Journal. 2020;56(1):1–3. https://doi.org/10.1183/13993003.01494-2020
  17. [doi: 10.1183/13993003.01494-2020]
  18. Korobova Z.R., Arsentieva N.A., Liubimova N.E., Batsunov O.K., Butenko A.A., Kokoeva A.E., Kucherenko N.G., Kashchenko V.A., Boeva E.V., Norka A.O., Knizhnikova A.A., Rassokhin V.V., Belyakov N.A., Totolian A.A. B Cell Dynamics and Transitional B Cells in Long COVID. Current Issues in Molecular Biology. 2025;47(4):245. https://doi.org/10.3390/cimb47040245
  19. [doi: 10.3390/cimb47040245]
  20. Lykhopiy V, Malviya V, Humblet-Baron S, Schlenner SM. IL-2 immunotherapy for targeting regulatory T cells in autoimmunity. Genes Immun. 2023 Oct;24(5):248-262. https://doi.org/10.1038/s41435-023-00221-y
  21. [doi: 10.1038/s41435-023-00221-y]
  22. Mobasheri L., Nasirpour M.H., Masoumi E., Azarnaminy A.F., Jafari M., Esmaeili S.A. SARS-CoV-2 triggers autoimmune diseases. Cytokine. 2022;154:155873. https://doi.org/10.1016/j.cyto.2022.155873
  23. [doi: 10.1016/j.cyto.2022.155873]
  24. Muhammad LN. Guidelines for repeated measures statistical analysis approaches with basic science research considerations. J Clin Invest. 2023 Jun 1;133(11):e171058. https://doi.org/10.1172/JCI171058
  25. [doi: 10.1172/JCI171058]
  26. NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19 (NG188): Evidence review 5: interventions. London: National Institute for Health and Care Excellence; 2020 Dec. https://www.nice.org.uk/guidance/ng188
  27. Putri D.U., Huang C.K., Ou T.Y., Lin C.F., Lee M.C., Hung C.S., Lee C.H. Persistent dysregulation of cellular immunity following COVID-19 recovery despite minimal post-COVID-19 sequelae manifestation. Journal of Infection. 2023;86(5):486–488. https://doi.org/10.1016/j.jinf.2023.02.025
  28. [doi: 10.1016/j.jinf.2023.02.025]
  29. Raeber ME, Sahin D, Karakus U, Boyman O. A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases. EBioMedicine. 2023 Apr;90:104539. https://doi.org/10.1016/j.ebiom.2023.104539
  30. [doi: 10.1016/j.ebiom.2023.104539]
  31. Savchenko A.A., Kudryavtsev I.V., Isakov D.V., Sadowski I.S., Belenyuk V.D., Borisov A.G. Recombinant Human Interleukin-2 Corrects NK Cell Phenotype and Functional Activity in Patients with Post-COVID Syndrome. Pharmaceuticals. 2023;16(4):537. https://doi.org/10.3390/ph16040537
  32. [doi: 10.3390/ph16040537]
  33. Shouse AN, LaPorte KM, Malek TR. Interleukin-2 signaling in the regulation of T cell biology in autoimmunity and cancer. Immunity. 2024 Mar 12;57(3):414-428. https://doi.org/10.1016/j.ebiom.2023.104539
  34. [doi: 10.1016/j.immuni.2024.02.001]
  35. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22(4):e102-e107. https://doi.org/10.1016/S1473-3099(21)00703-9
  36. [doi: 10.1016/S1473-3099(21)00703-9]
  37. WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infectious Diseases. 2020;20:e192–e197. https://doi.org/10.1016/S1473-3099(20)30483-7
  38. [doi: 10.1016/S1473-3099(20)30483-7]
  39. Yin K, Peluso MJ, Luo X, Thomas R, Shin MG, Neidleman J, Andrew A, Young KC, Ma T, Hoh R, Anglin K, Huang B, Argueta U, Lopez M, Valdivieso D, Asare K, Deveau TM, Munter SE, Ibrahim R, Ständker L, Lu S, Goldberg SA, Lee SA, Lynch KL, Kelly JD, Martin JN, Münch J, Deeks SG, Henrich TJ, Roan NR. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat Immunol. 2024 Feb;25(2):218-225. https://doi.org/10.1038/s41590-023-01724-6
  40. [doi: 10.1038/s41590-023-01724-6]

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