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The influence of humoral factors of homeostatistic proliferation on t-regulatory cells in vitro

https://doi.org/10.20538/1682-0363-2019-1-286-293

Abstract

Aim. The aim of this study was the investigation of the influence of humoral factors of homeostatic proliferation IL-7 and IL-15 on T-regulatory cells in healthy donors.

Materials and methods. The study included 15 conditionally healthy donors. Phenotyping and evaluation of expression changes of transcription factor FoxP3 and the main functional molecules on T-regulatory cells such as PD-L1, CTLA-4 and HLA-DR during cultivation under IL-7, IL-15 and anti-CD3 stimulation combined with IL-2 were performed by flow cytometry. Also, we estimated proliferation intensity of T-regulatory cells in the course of cultivation.

Results. We revealed that humoral factors of homeostatic proliferation can effectively support a pool of T-regulatory cells during cultivation by number and phenotype and can maintain expression of important molecules such as PD-L1 and HLA-DR on regulatory T-cell surface. In addition, our study showed that IL-7 and IL-15 can cause relatively low T-regulatory cells proliferation in comparison to CD4+- lymphocytes.

Conclusion. The observed ability of homeostatic proliferation factors to maintain T-regulatory cells pool presumably can play an important role in lymphopenic conditions when the number of effector cells is decreased and the insufficiency of interleukin IL-2 is observed, which plays a primary role in the homeostasis of T-regulatory cells in normal conditions.

About the Authors

D. V. Shevyrev
Research Institute of Fundamental and Clinical Immunology (RIFCI)
Russian Federation

Shevyrev Daniil V., PhD Student, Laboratory of Clinical Immunopathology

14, Yadrintsevskaya Str., Novosibirsk, 630099



E. A. Blinova
Research Institute of Fundamental and Clinical Immunology (RIFCI)
Russian Federation

Blinova Elena A., PhD, Senior Researcher, Laboratory of Clinical Immunopathology

14, Yadrintsevskaya Str., Novosibirsk, 630099



V. A. Kozlov
Research Institute of Fundamental and Clinical Immunology (RIFCI)
Russian Federation

Kozlov Vladimir A., DM, Professor, Аcademician of RAS, Scientific Supervisor of RIFCI, Head of the Laboratory of Clinical Immunopathology, RIFCI

14, Yadrintsevskaya Str., Novosibirsk, 630099



References

1. Moxham V.F., Karegli J., Phillips R.E., Brown K.L., Tapmeier T.T., Hangartner R., Sacks S.H., Wong W. Homeostatic proliferation of lymphocytes results in augmented memory-like function and accelerated allograft rejection. J. Immunol. 2008; Mar. 15; 180 (6): 3910–3918. DOI: 10.4049/jimmunol.180.6.3910.

2. Bolton H.A., Zhu E., Terry A.M., Guy T.V., Koh W.P., Tan S.Y., Power C.A., Bertolino P., Lahl K., Sparwasser T., Shklovskaya E., Fazekas de St Groth B. Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease. J. Clin. Invest. 2015; 125 (9): 3627–3641. DOI: 10.1172/JCI76031.

3. Miller C.N., Hartigan-O’Connor D.J., Lee M.S., Laidlaw G., Cornelissen I. P., Matloubian M., Coughlin S.R., McDonald D.M., McCune J.M. IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. Int. Imm. 2013; 25 (8): 471–483. DOI: 10.1093/intimm/dxt012.

4. Schluns K.S., Rivas S., Stonier S.W, Colpitts S.L., Anthony S.M. Expression of IL-15 is differentially regulated during lymphopenia depending on the method of induction. The Journal of Immunology. 2016; May 1, 196 (1 Supplement): 196.15.

5. Theofilopoulos A.N., Dummer W., Kono D.H. T cell homeostasis and systemic autoimmunity. The Journal of Сlinical Investigation. 2001; 108 (3): 335–340. DOI: 10.1172/JCI12173.

6. Ge Q., Rao V.P., Cho B.K., Eisen H.N., Chen J. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/MHC epitopes and strength of their interaction with T cell receptors. Proc. Natl. Acad. Sci. USA. 2001; 98 (4): 1728–1733. DOI: 10.1073/pnas.98.4.1728.

7. Kieper W.C., Burghardt J.T., Surh C.D. A role for TCR affinity in regulating naive T cell homeostasis. J. Immunol. 2004; 172 (1): 40–44. DOI: 10.4049/jimmunol.172.1.40.

8. Jones J.L., Thompson S.A.J., Loh P., Davies J.L., Tuohy O.C., Curry A.J., Azzopardi L., Hill-Cawthorne G., Fahey M.T., Compston A., Coles A.J. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. PNAS. 2013, 110 (50): 20200-02025. DOI: 10.1073/pnas.1313654110.

9. Komatsu N., Okamoto K., Sawa S., Nakashima T.,Oh-hora M., Kodama T., Tanaka S., Bluestone J.A., Takayanagi H. Pathogenic conversion of Foxp3+ T-cells into TH17 cells in autoimmune arthritis. Nat. Med. 2014; 20 (1): 62–70. DOI: 10.1038/nm.3432.

10. Duarte J.H., Zelenay S., Bergman M.L., Martins A.C., Demengeot J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur. J. Immunol. 2009; 39: 948–955. DOI: 10.1002/eji.200839196.

11. Chevalier N., Thorburn A.N., Macia L., Tan J., Juglair L., Yagita H., Yu D., Hansbro P.M., Mackay C.R. Inflammation and lymphopenia trigger autoimmunity by suppression of IL-2-controlled regulatory T cell and increase of IL-21-mediated effector T cell expansion. J. Immunol. 2014; 193 (10): 4845–4858. DOI: 10.4049/jimmunol.1302966.

12. Bayer A.L., Lee J.Y., de la Barrera A., Surh C.D., Malek T.R. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 2008; 181 (1): 225–234.

13. Simonetta F., Gestermann N., Martinet K.Z., Boniotto M., Tissiиres P., Seddon B., Bourgeois C. Interleukin-7 influences FOXP3+CD4+ regulatory T cells peripheral homeostasis. PLoS One. 2012; 7 (5): e36596. DOI: 10.1371/journal.pone.0036596.

14. Younas M., Hue S., Lacabaratz C., Guguin A., Wiedemann A., Surenaud M., Beq S., Croughs T., Leliиvre J.D., Lévy Y. IL-7 modulates in vitro and in vivo human memory T regulatory cell functions through the CD39/ ATP axis. J. Immunol. 2013; Sep. 15; 191 (6): 3161–3168. DOI: 10.4049/jimmunol.1203547.

15. Xia J., Liu W., Hu B., Tian Z., Yang Y. IL-15 promotes regulatory T cell function and protects against diabetes development in NK-depleted NOD mice. Clin. Immunol. 2010; 134 (2): 130–139. DOI: 10.1016/j.clim.2009.09.011.

16. Ben A.M., Belhadj H.N., Moes N., Buyse S., Abdeladhim M., Louzir H., Cerf-Bensussan N. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J. Immunol. 2009, 182 (11): 6763–6770. DOI: 10.4049/jimmunol.0801792.

17. Suzuki H., Kündig T.M., Furlonger C., Wakeham A., Timms E., Matsuyama T., Schmits R., Simard J.J., Ohashi P.S., Griesser H. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science. 1995, 268 (5216): 1472–1476.

18. Malek T.R., Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 2010. 33 (2): 153–165. DOI: 10.1016/j.immuni.2010.08.004.

19. Chinen T., Kannan A.K., Levine A.G., Fan X., Klein U., Zheng Y., Gasteiger G., Feng Y., Fontenot J.D., Rudensky A.Y. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 2016; Nov. 17 (11): 1322– 1333. DOI: 10.1038/ni.3540.

20. Sharfe N., Dadi H.K., Shahar M., Roifman C.M. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc. Natl. Acad. Sci. USA. 1997; 94 (7): 3168–3171.

21. Goudy K., Aydin D., Barzaghi F., Gambineri E., Vignoli M., Ciullini M.S., Doglioni C., Ponzoni M., Cicalese M.P., Assanelli A., Tommasini A., Brigida I., Dellepiane R.M., Martino S., Olek S., Aiuti A., Ciceri F., Roncarolo M.G., Bacchetta R. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin. Immunol. 2013; Mar. 146 (3): 248–261. DOI: 10.1016/j.clim.2013.01.004.

22. Jeon P.H., Oh K.I. IL2 is required for functional maturation of regulatory T cells. Animal Cells and Systems. 2017, 21 (1): 1–9. DOI: 10.1080/19768354.2016.1272489.

23. Owen D.L., Mahmud S.A., Vang K.B., Kelly R.M., Blazar B.R., Smith K.A., Farrar M.A. Identification of сellular sources of IL-2 needed for regulatory T сell development and homeostasis. J. Immunol. 2018; Jun. 15; 200 (12): 3926–3933. DOI: 10.4049/jimmunol.1800097.

24. Almeida A.R., Zaragoza B., Freitas A.A. Indexation as a novel mechanism of lymphocyte homeostasis: the number of CD4+CD25+ regulatory T cells is indexed to the number of IL-2-producing cells. J. Immunol. 2006; 177 (1): 192–200.

25. Vang K.B., Yang J., Mahmud S.A., Burchill M.A.,Vegoe A.L., Farrar M.A. Interleukin-2, -7 and -15, but not TSLP, redundantly govern CD4+Foxp3+ regulatory T сell development. J. Immunol. 2008; Sep. 1, 181 (5): 3285–3290

26. Jain N., Nguyen H., Chambers C., Kang J. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc. Nat. Acad. Sci. USA. 2010; Jan. 26; 107 (4): 1524–1528. DOI: 10.1073/pnas.0910341107.

27. Dai S., Jia R., Zhang X., Fang Q., Huang L. The PD-1/ PD-Ls pathway and autoimmune diseases. Cell Immunol. 2014; Jul. 290 (1): 72–79. DOI: 10.1016/j.cellimm.2014.05.006.

28. Francisco L.M., Salinas V.H., Brown K.E., Vanguri V.K., Freeman G.J., Kuchroo V.K., Sharpe A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 2009; Dec. 2; 206. (13): 3015–3029. DOI: 10.1084/jem.20090847.

29. Kinter A.L., Godbout E.J., McNally J.P., Sereti I., Roby G.A., O’Shea M.A., Fauci A.S. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 2008; Nov. 15, 181 (10): 6738–6746.

30. Baecher-Allan C., Wolf E., Hafler D.A. MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol. 2006; Apr. 15; 176 (8): 4622–4631.

31. Zou T., Caton A.J. Dendritic сells induce regulatory T cell proliferation through antigen-dependent and independent interactions. The Journal of Immunology. 2010; 185 (5): 2790–2799. DOI: 10.4049/jimmunol.0903740.

32. Zou T., Satake A., Corbo E., Schmidt A.M., Farrar M.A., Maltzman J.S., Kambayashi T. Cutting edge: IL-2 signals determine the degree of TCR signaling necessary to support regulatory T cell proliferation in vivo. J. Immunol. 2012; 189 (1): 28–32. DOI: 10.4049/jimmunol.1200507.

33. Nishio J., Feuerer M., Wong J., Mathis D., Benoist C. Anti-CD3 therapy permits regulatory T cells to surmount T cell receptor-specified peripheral niche constraints. J. Exp. Med. 2010; 207 (9):1879–1889. DOI: 10.1084/jem.20100205.

34. Walker L.S., Chodos A., Eggena M., Dooms H., Abbas A.K. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 2003; Jul. 21;198 (2): 249–258.


Review

For citations:


Shevyrev D.V., Blinova E.A., Kozlov V.A. The influence of humoral factors of homeostatistic proliferation on t-regulatory cells in vitro. Bulletin of Siberian Medicine. 2019;18(1):286-293. (In Russ.) https://doi.org/10.20538/1682-0363-2019-1-286-293

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ISSN 1682-0363 (Print)
ISSN 1819-3684 (Online)