The in vitro effect of dexamethasone on maturation and differentiation of CD4+CD45RO+ T-cells in rheumatoid arthritis
Keywords:
memory T-cells; rheumatoid arthritis; glucocorticoid hormone; dexamethasone; activation; differentiation; maturation.
Abstract
Aim. To study the effect of dexamethasone (Dex) on activation and generation of terminally differentiated effector CD4+ T-lymphocytes (TEMRA) in cultured CD3+CD45RO+ T cells under the conditions mimicking stimulation of the T-cell receptor in vitro as it occurs in health and rheumatoid arthritis (RA). Methods. The study was performed on mononuclear leukocytes isolated from heparinized venous blood of 50 patients with rheumatoid arthritis. Changes in the T-lymphocyte immunophenotype were detected using flow cytofluorometry. Secretion of cytokine IL-2 by CD3+ CD45ROT+ cells was assessed by ELISA. Expression of hTERT, U2af1l4, and Gfi1 gene mRNA in CD3+CD45RO+ T cells was measured by polymerase chain reaction. Results. During the in vitro TCR activation of cultured CD3+CD45RO+ T cells, Dex participated to a variable extent in formation of a subpopulation of terminally differentiated effectors (CD3+CD4+CD45RO-CD28- TEMRA), which are characterized by low telomerase activity, loss of costimulation (CD28) and activation (CD25) molecules, and re-expression of the high molecular weight CD45-CD45RA receptor isoform both in healthy individuals and RA patients. Conclusion. The population of CD3+CD4+CD45RO-CD28- lymphocytes is a key participant in the pathogenesis of RA by accelerating their negative impact during the glucocorticoid therapy. This lymphocyte population contributes to RA progression particularly due to the powerful discharge of proinflammatory mediators.
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References
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32. Liberman A.C., Refojo D., Druker J., Toscano M., Rein T., Holsboer F. et al. The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. Faseb J. 2007; 21 (4): 1177-1188 .
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37. Fujii H., Shao L., Colmegna I., Goronzy J.J., Weyand C.M. Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci USA. 2009; 106 (11): 4360-4365.
2. Mateen S., Zafar A., Moin S., Khan A.Q., Zubair S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 2016; 455: 161-171.
3. VanderBorght A., Geusens P., Raus J., Stinissen P. The autoimmune pathogenesis of rheumatoid arthritis: role of autoreactive T cells and new immunotherapies. Semin Arthritis Rheum. 2001; 31(3): 160-175.
4. Spreafico R., Rossetti M., Whitaker J.W., Wang W., Lovell D.J., Albani S. Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+ T cell activation pathways. Proc Natl Acad Sci U S A. 2016; 113(48): 13845-13850.
5. Thewissen M., Linsen L., Somers V., Geusens P., Raus J., Stinissen P. Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann N Y Acad Sci. 2005; 1051: 255-262.
6. Тодосенко Н.М., Хазиахматова О.Г., Юрова К.А., Малинина И.П., Литвинова Л.С. Влияние метилпреднизолона на процессы активации CD4+CD45RO+ Т-клеток при ревматоидном артрите (in vitro). Цитология. 2017; 59 (6): 421-427.
7. Heyd F., ten Dam G., Mоrоy T. Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing. Nat. Immunol. 2006; 7 (8): 859-867.
8. Butte M.J., Lee S.J., Jesneck J., Keir M.E., Haining W.N., Sharpe A.H. CD28 costimulation regulates genome-wide effects on alternative splicing. PLoS ONE. 2012; 7 (6): e40032.
9. Юрова К.А., Хазиахматова О.Г., Сохоневич Н.А., Гончаров А.Г., Литвинова Л.С. Альтернативный сплайсинг молекулы CD45 в механизмах молекулярно-генетического контроля дифференцировки Т-клеток. Российский иммунологический журнал. 2015; 9 (: 186-193.
10. Baschant U., Tuckermann J. The role of the glucocorticoid receptor in inflammation and immunity. J. Steroid Biochem. Mol. Biol. 2010; 120 (2-3): 69-75.
11. Gutsol A.A., Sokhonevich N.A., Yurova K.A., Khaziakhmatova O.G., Shupletsova V.V., Litvinova L.S. Dose-dependent effects of dexamethasone on functional activity of T-lymphocytes with different grades of differentiation. Molecular Biology. 2015; 49 (1): 130-137.
12. Jeong H., Baek S.Y., Kim S.W., Eun Y.H., Kim I.Y., Kim H. et al. Comorbidities of rheumatoid arthritis: Results from the Korean National Health and Nutrition Examination Survey. PLoS One. 2017; 12 (4): e0176260.
13. Anderson A.E., Swan D.J., Wong O.Y., Buck M., Eltherington O., Harry R.A. et al. Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-b1. Clin Exp Immunol. 2017; 187 (1); 113-123.
14. Сытыбалдиев А.М. Лечение ревматической полимиалгии. Современная ревматология. 2013; 1: 66-72.
15. Motamedi M., Xu L., Elahi S. Correlation of transferrin receptor (CD71) with Ki67 expression on stimulated human and mouse T cells: The kinetics of expression of T cell activation markers. J Immunol Methods. 2016; 437: 43-52.
16. Kim H.P., Imbert J., Leonard W.J. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006; 17 (5): 349-366.
17. Miller J., Baker C., Cook K., Graf B., Sanchez-Lockhart M., Sharp K. et al. Two pathways of costimulation through CD28. Immunol Res. 2009; 45 (2-3): 159-172.
18. Beyersdorf N., Kerkau T., Hunig T. CD28 co-stimulation in T-cell homeostasis: a recent perspective. Immunotargets Ther. 2015; 4: 111-122.
19. Marsee D.K., Pinkus G.S., Yu H. CD71 (transferrin receptor): an effective marker for erythroid precursors in bone marrow biopsy specimens. Am J Clin Pathol. 2010; 134 (3): 429-435.
20. Литвинова Л.С., Гуцол А.А., Сохоневич Н.А., Кофанова К.А., Хазиахматова О.Г., Шуплецова В.В. и др. Основные поверхностные маркеры функциональной активности Т-лимфоцитов. Медицинская иммунология. 2014; 16 (1): 7-26.
21. Stauber D.J., Debler E.W., Horton P.A., Smith K.A., Wilson I.A. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci USA. 2006; 103 (8): 2788-2793.
22. Goudy K., Aydin D., Barzaghi F., Gambineri E., Vignoli M., Ciullini Mannurita S. et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013; 146 (3): 248-261.
23. Horikawa I., Barrett J.C. Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis. 2003; 24 (7): 1167-1176.
24. Weyand C.M., Fujii H., Shao L., Goronzy J.J. Rejuvenating the immune system in rheumatoid arthritis. Nat Rev Rheumatol. 2009; 5 (10): 583-588.
25. Koetz K., Bryl E., Spickschen K., O’Fallon W.M., Goronzy J.J., Weyand C.M. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA. 2000; 97 (16): 9203-9208.
26. Matsuki F., Saegusa J., Miyamoto Y., Misaki K., Kumagai S., Morinobu A. CD45RA-Foxp3(high) activated/effector regulatory T cells in the CCR7 + CD45RA-CD27 + CD28+central memory subset are decreased in peripheral blood from patients with rheumatoid arthritis. Biochem Biophys Res Commun. 2013; 438 (4): 778-783.
27. Ярилин А.А. Иммунология. М.: ГЭОТАР-Медиа, 2010.
28. Yurova K.A., Sokhonevich N.A., Khaziakhmatova O.G., Litvinova L.S. Cytokine-mediated of expression of Gfi1 and U2afll4 genes by activated T-cells with various differentiation status in vitro. Biochemistry (Moscow) Supplement series B: Biomedical Chemistry. 2015; 9 (2): 165-172.
29. Makrygiannakis D., Revu S., Neregаrd P., af Klint E., Snir O., Grundtman C. et al. Monocytes are essential for inhibition of synovial T-cell glucocorticoid-mediated apoptosis in rheumatoid arthritis. Arthritis Res Ther. 2008; 10 (6): R147.
30. Davis T.E., Kis-Toth K., Szanto A., Tsokos G.C. Glucocorticoids suppress T cell function by up-regulating microRNA-98. Arthritis Rheum. 2013; 65 (7): 1882-1890.
31. Baschant U., Tuckermann J. The role of the glucocorticoid receptor in inflammation and immunity. J Steroid Biochem Mol Biol. 2010; 120 (2-3): 69-75.
32. Liberman A.C., Refojo D., Druker J., Toscano M., Rein T., Holsboer F. et al. The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. Faseb J. 2007; 21 (4): 1177-1188 .
33. Elshabrawy H.A., Chen Z., Volin M.V., Ravella S., Virupannavar S., Shahrara S. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 2015; 18 (4): 433-448.
34. Pieper J., Johansson S., Snir O., Linton L., Rieck M., Buckner J.H. et al. Peripheral and site-specific CD4 + CD28 null T cells from rheumatoid arthritis patients show distinct characteristics. Scand J Immunol. 2014; 79 (2): 149-155.
35. van Leeuwen E.M., Remmerswaal E.B., Vossen M.T., Rowshani A.T., Wertheim-van Dillen P.M., van Lier R.A., ten Berge I.J. Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. Journal of immunology. 2004, 173(3), 1834-1841.
36. Vallejo A.N., Schirmer M., Weyand C.M., Goronzy J.J. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. Journal of immunology. 2000; 165 (11): 6301-6307.
37. Fujii H., Shao L., Colmegna I., Goronzy J.J., Weyand C.M. Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci USA. 2009; 106 (11): 4360-4365.
Published
2017-12-18
How to Cite
Todosenko N. M., Yurova K. A., Khaziakhmatova O. G., Malinina I. P., Litvinova L. S. The in vitro effect of dexamethasone on maturation and differentiation of CD4+CD45RO+ T-cells in rheumatoid arthritis // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2017. VOL. 61. № 4. PP. 87–97.
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Original research
