kpcczКомплексные проблемы сердечно-сосудистых заболеванийComplex Issues of Cardiovascular Diseases2306-12782587-9537Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”10.17802/2306-1278-2020-9-2-82-90kpccz-718Research ArticleАНАЛИТИЧЕСКИЙ ОБЗОРANALYTICAL REVIEWРоль регуляторных Т-клеток в системном воспалительном ответеRole of regulatory T-cells in the systemic inflammatory response syndromehttps://orcid.org/0000-0002-8826-9244ХановаМ. Ю.KhanovaM. Yu.

Ханова Марьям Юрисовна - младший научный сотрудник лаборатории клеточных технологий.

Сосновый бульвар, 6, Кемерово, 650002

Khanova Mariam Yu. - research assistant at the Laboratory of Cell Technologies.

6, Sosonoviy Blvd., Kemerovo, 650002

khanovam@gmail.comhttps://orcid.org/0000-0002-4146-3373МатвееваВ. Г.MatveevaV. G.

Матвеева Вера Геннадьевна - кандидат медицинских наук, старший научный сотрудник лаборатории клеточных технологий.

Сосновый бульвар, 6, Кемерово, 650002

Matveeva Vera G. - PhD, senior researcher at the Laboratory of Cell Technologies.

6, Sosonoviy Blvd., Kemerovo, 650002

https://orcid.org/0000-0002-8874-0788АнтоноваЛ. В.AntonovaL. V.

Антонова Лариса Валерьевна - доктор медицинских наук, заведующая лабораторией клеточных технологий.

Сосновый бульвар, 6, Кемерово, 650002

Antonova Larisa V. - PhD, Head of the Laboratory of Cell Technologies.

6, Sosonoviy Blvd., Kemerovo, 650002

https://orcid.org/0000-0001-8370-3083ГригорьевЕ. В.GrigorievE. V.

Григорьев Евгений Валерьевич - доктор медицинских наук, профессор, заместитель директора по научной и лечебной работе, ведущий научный сотрудник.

Сосновый бульвар, 6, Кемерово, 650002

Grigoriev Evgeny V. - PhD, Professor of the Russian Academy of Sciences, Deputy Director for Scientific and Medical Issues.

6, Sosonoviy Blvd., Kemerovo, 650002

Федеральное государственное бюджетное научное учреждение Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеванийРоссияFederal State Budgetary Institution Research Institute for Complex Issues of Cardiovascular DiseasesRussian Federation202024062020928290Copyright © Ханова М.Ю., Матвеева В.Г., Антонова Л.В., Григорьев Е.В., 20202020Ханова М.Ю., Матвеева В.Г., Антонова Л.В., Григорьев Е.В.Khanova M.Y., Matveeva V.G., Antonova L.V., Grigoriev E.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nii-kpssz.com/jour/article/view/718

Системный воспалительный ответ - сложный мультисиндромный, фазоспецифичный патологический процесс, развивающийся при системном повреждении. Исход во многом зависит от баланса разнонаправленных последовательных стадий: гипервоспалительной реакции и компенсаторного антивоспалительного механизма. Регуляторные T-клетки (Tregs) способны ограничивать адаптивные и врожденные иммунные реакции и вносить свой вклад в различные этапы системного воспалительного ответа. На начальной гипервоспалительной стадии Tregs способны ограничивать аутогенное повреждение. Однако в последующем Tregs способствуют развитию компенсаторного антивоспалительного механизма и формированию индуцированной иммуносупрессии, которая предрасполагает к высокой восприимчивости к нозокомиальным и оппортунистическим инфекциям с последующим переходом в полиорганную недостаточность. Регуляторные Т-клетки и их функциональные изменения рассматриваются как диагностические и прогностические маркеры осложнений системного воспалительного ответа.

Systemic inflammatory response syndrome is a complex multisyndromic, phase-specific pathological process that develops with systemic damage. Outcomes largely depend on the balance of multidirectional sequential stages: hyperinflammatory reaction and compensatory anti-inflammatory response syndrome (CARS). Regulatory T-cells (Tregs) are able to regulate adaptive and innate immune responses and contribute to the various stages ofthe systemic inflammatory response syndrome. At the initial hyperinflammatory stage, Tregs are able to limit self-inflicted damage. At the same time, Tregs contribute to CARS and the formation of induced immunosuppression, predisposing to a high susceptibility to nosocomial and opportunistic infections, with subsequent transition to multiple organ dysfunction syndrome. Regulatory T-cells and their functional changes are considered as predictors and prognostic markers of critical illness.

Системный воспалительный ответРегуляторные Т-клеткиИммуносупрессияSystemic inflammatory response syndromeRegulatory T-cellsImmunosuppressionРабота выполнена при поддержке комплексной программы фундаментальных научных исследований СО РАН в рамках фундаментальной темы НИИ КПССЗ № 0546-2015-0011 «Патогенетическое обоснование разработки имплантатов для сердечно-сосудистой хирургии на основе биосовместимых материалов с реализацией пациент-о-риентированного подхода с использованием математического моделирования, тканевой инженерии и геномных предикторов»ReferencesBone R.C. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med. 1996; 125 (8): 680-687. doi: 10.7326/0003-4819-125-8-199610150-00009Bone R.C. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med. 1996; 125 (8): 680-687. doi: 10.7326/0003-4819-125-8-199610150-00009Sakaguchi S., Sakaguchi N., Shimizu J., Yamazaki S., Sakihama T., Itoh M., Kuniyasu Y, Nomura T., Toda M., Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001; 182 (1): 18-32. doi:10.1034/j.1600-065X.2001.1820102.xSakaguchi S., Sakaguchi N., Shimizu J., Yamazaki S., Sakihama T., Itoh M., Kuniyasu Y, Nomura T., Toda M., Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001; 182 (1): 18-32. doi:10.1034/j.1600-065X.2001.1820102.xAbbas A.K., Benoist C., Bluestone J.A., Campbell D.J., Ghosh S., Hori S., Jiang S., Kuchroo V.K., Mathis D., Roncarolo M.G., Rudensky A., Sakaguchi S., Shevach E.M., Vignali D.A., Ziegler S.F. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013; 14 (4): 307308. doi:10.1038/ni.2554. DOI: 10.1038/ni.2554Abbas A.K., Benoist C., Bluestone J.A., Campbell D.J., Ghosh S., Hori S., Jiang S., Kuchroo V.K., Mathis D., Roncarolo M.G., Rudensky A., Sakaguchi S., Shevach E.M., Vignali D.A., Ziegler S.F. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013; 14 (4): 307308. doi:10.1038/ni.2554. DOI: 10.1038/ni.2554Fehervari Z., Sakaguchi S. CD4(+) Tregs and immune control. Clin. Invest. 2004; 114 (9): 1209-1217. doi:10.1172/JCI200423395Fehervari Z., Sakaguchi S. CD4(+) Tregs and immune control. Clin. Invest. 2004; 114 (9): 1209-1217. doi:10.1172/JCI200423395Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control immune responses. Annu Rev Immunol. 2004; 22: 531-562. doi:10.1146/annurev.immunol.21.120601.141122Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control immune responses. Annu Rev Immunol. 2004; 22: 531-562. doi:10.1146/annurev.immunol.21.120601.141122Gershon R.K., Kondo K. Infectious immunological tolerance. Immunology. 1971; 21 (6): 903-914.Gershon R.K., Kondo K. Infectious immunological tolerance. Immunology. 1971; 21 (6): 903-914.Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alfa-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995; 155: 1151-1164.Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alfa-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995; 155: 1151-1164.Baecher-Allan C., Brown J.A., Freeman G.J., Hafler D.A. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001; 167 (3): 1245-1253. doi:10.4049/jimmunol.167.3.1245Baecher-Allan C., Brown J.A., Freeman G.J., Hafler D.A. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001; 167 (3): 1245-1253. doi:10.4049/jimmunol.167.3.1245Yagi H., Nomura T., Nakamura K., Yamazaki S., Kitawaki T., Hori S., Maeda M., Onodera M., Uchiyama T., Fujii S., Sakaguchi S. Crucial role of FOXP3 in the development and function of human CD4+CD25+regulatory T cells. Int. Immunol. 2004; 16 (11): 1643-1656. doi:10.1093/intimm/dxh165Yagi H., Nomura T., Nakamura K., Yamazaki S., Kitawaki T., Hori S., Maeda M., Onodera M., Uchiyama T., Fujii S., Sakaguchi S. Crucial role of FOXP3 in the development and function of human CD4+CD25+regulatory T cells. Int. Immunol. 2004; 16 (11): 1643-1656. doi:10.1093/intimm/dxh165Jiang S., Lechler R.I., He X.S., Huang J.F. Regulatory T cells and transplantation tolerance. Hum. Immunol. 2006; 67 (10): 765-776. doi:10.1016/j.humimm.2006.07.013Jiang S., Lechler R.I., He X.S., Huang J.F. Regulatory T cells and transplantation tolerance. Hum. Immunol. 2006; 67 (10): 765-776. doi:10.1016/j.humimm.2006.07.013Liu W., Putnam A.L., Xu,Yu Z., Szot G.L., Lee M.R., Zhu S., Gottlieb P.A., Kapranov P., Gingeras T.R., Fazekas de St Groth B., Clayberger C., Soper D.M., Ziegler S.F., Bluestone J.A. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006; 203 (7): 1701-1711. doi:10.1084/jem.20060772Liu W., Putnam A.L., Xu,Yu Z., Szot G.L., Lee M.R., Zhu S., Gottlieb P.A., Kapranov P., Gingeras T.R., Fazekas de St Groth B., Clayberger C., Soper D.M., Ziegler S.F., Bluestone J.A. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006; 203 (7): 1701-1711. doi:10.1084/jem.20060772Shen L.S., Wang J., Shen D.F. Yuan X.L., Dong P., Li M.X., Xue J., Zhang F.M., Ge H.L., Xu D. CD4+CD25+CD127low/- regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression. Clin Immunol. 2009; 131 (1): 109-118. doi:10.1016/j.clim.2008.11.010Shen L.S., Wang J., Shen D.F. Yuan X.L., Dong P., Li M.X., Xue J., Zhang F.M., Ge H.L., Xu D. CD4+CD25+CD127low/- regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression. Clin Immunol. 2009; 131 (1): 109-118. doi:10.1016/j.clim.2008.11.010Banham A.H. Cell-surface IL-7 receptor expression facilitates the purification of FOXP3(+) regulatory T cells. Trends Immunol. 2006; 27 (12): 541-544. doi:10.1016/j.it.2006.10.002Banham A.H. Cell-surface IL-7 receptor expression facilitates the purification of FOXP3(+) regulatory T cells. Trends Immunol. 2006; 27 (12): 541-544. doi:10.1016/j.it.2006.10.002Taams L.S., Van Amelsfort J.M., Tiemessen M.M., Jacobs K.M., de Jong E.C., Akbar A.N., Bijlsma J.W., Lafeber F.P. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Imunol. 2005; 66 (3): 222-230. doi:10.1016/j.humimm.2004.12.006Taams L.S., Van Amelsfort J.M., Tiemessen M.M., Jacobs K.M., de Jong E.C., Akbar A.N., Bijlsma J.W., Lafeber F.P. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Imunol. 2005; 66 (3): 222-230. doi:10.1016/j.humimm.2004.12.006Piccirillo C.A., Shevach E.M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Imunol. 2001; 167 (3): 1137-1140. doi:10.4049/jimmunol.167.3.1137Piccirillo C.A., Shevach E.M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Imunol. 2001; 167 (3): 1137-1140. doi:10.4049/jimmunol.167.3.1137Collison L.W., Workman C.J., Kuo T.T., Boyd K., Wang Y., Vignali K.M., Cross R., Sehy D., Blumberg R.S. Vignali D.A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007; 450 (7169): 566-569. doi:10.1038/nature06306Collison L.W., Workman C.J., Kuo T.T., Boyd K., Wang Y., Vignali K.M., Cross R., Sehy D., Blumberg R.S. Vignali D.A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007; 450 (7169): 566-569. doi:10.1038/nature06306Shull M.M., Ormsby I., Kier A.B., Pawlowski S., Diebold R.J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D., Annunziata N., Doetschman T. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359 (6397): 693-699. doi:10.1038/359693a0Shull M.M., Ormsby I., Kier A.B., Pawlowski S., Diebold R.J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D., Annunziata N., Doetschman T. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359 (6397): 693-699. doi:10.1038/359693a0Brabletz T., Pfeuffer I., Schorr E., Siebelt F., Wirth T., Serfling E. Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol. 1993; 13 (2): 1155-1162. doi:10.1128/MCB.13.2.1155Brabletz T., Pfeuffer I., Schorr E., Siebelt F., Wirth T., Serfling E. Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol. 1993; 13 (2): 1155-1162. doi:10.1128/MCB.13.2.1155Moore K.W., de Waal Malefyt R., Coffman R.L., O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001; 19: 683-765. doi:10.1146/annurev.immunol.19.1.683Moore K.W., de Waal Malefyt R., Coffman R.L., O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001; 19: 683-765. doi:10.1146/annurev.immunol.19.1.683Kuhn R., Lohler J., Rennick D., Rajewsky K., Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993; 75 (2): 263-274. doi:10.1016/0092-8674(93)80068-PKuhn R., Lohler J., Rennick D., Rajewsky K., Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993; 75 (2): 263-274. doi:10.1016/0092-8674(93)80068-PMisra N., Bayry J., Lacroix-Desmazes S., Kazatchkine M.D., Kaveri S.V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol. 2004; 172 (8): 4676-4680. doi:10.4049/jimmunol.172.8.4676Misra N., Bayry J., Lacroix-Desmazes S., Kazatchkine M.D., Kaveri S.V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol. 2004; 172 (8): 4676-4680. doi:10.4049/jimmunol.172.8.4676Grohmann U., Orabona C., Fallarino F., Vacca C., Calcinaro F., Falorni A., Candeloro P., Belladonna M.L., Bianchi R., Fioretti M.C., Puccetti P. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology. 2002; 3 (11), 1097-1101. doi:10.1038/ni846Grohmann U., Orabona C., Fallarino F., Vacca C., Calcinaro F., Falorni A., Candeloro P., Belladonna M.L., Bianchi R., Fioretti M.C., Puccetti P. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology. 2002; 3 (11), 1097-1101. doi:10.1038/ni846Liang B., Workman C., Lee J., Chew C., Dale B.M., Colonna L., Flores M., Li N., Schweighoffer E., Greenberg S., Tybulewicz V, Vignali D., Clynes R. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol. 2008; 180 (9): 5916-5926. doi:10.4049/jimmunol.180.9.5916Liang B., Workman C., Lee J., Chew C., Dale B.M., Colonna L., Flores M., Li N., Schweighoffer E., Greenberg S., Tybulewicz V, Vignali D., Clynes R. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol. 2008; 180 (9): 5916-5926. doi:10.4049/jimmunol.180.9.5916Walker L.S. K., Sansom D.M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nature Reviews Immunology. 2011; 11: 852-863. doi:10.1038/nri3108Walker L.S. K., Sansom D.M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nature Reviews Immunology. 2011; 11: 852-863. doi:10.1038/nri3108Qureshi O.S., Zheng Y., Nakamura K., Attridge K., Manzotti C., Schmidt E.M., Baker J., Jeffery L.E., Kaur S., Briggs Z., Hou T.Z., Futter C.E., Anderson G., Walker L.S.K., Sansom D.M. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell extrinsic function of CTLA-4. Science. 2011; 332 (6029): 600-603. doi:10.1126/science.1202947Qureshi O.S., Zheng Y., Nakamura K., Attridge K., Manzotti C., Schmidt E.M., Baker J., Jeffery L.E., Kaur S., Briggs Z., Hou T.Z., Futter C.E., Anderson G., Walker L.S.K., Sansom D.M. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell extrinsic function of CTLA-4. Science. 2011; 332 (6029): 600-603. doi:10.1126/science.1202947Gondek D.C., Lu L.F., Quezada S.A., Sakaguchi S., Noelle R.J.. Cutting Edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol. 2005; 174 (4): 1783-1786. doi:10.4049/jimmunol.174.4.1783Gondek D.C., Lu L.F., Quezada S.A., Sakaguchi S., Noelle R.J.. Cutting Edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol. 2005; 174 (4): 1783-1786. doi:10.4049/jimmunol.174.4.1783Grossman W.J., Verbsky J.W., Barchet W., Collona M., Atkinson J.P., Ley T.J. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004; 21 (4): 589-601. doi:10.1016/j.immuni.2004.09.002Grossman W.J., Verbsky J.W., Barchet W., Collona M., Atkinson J.P., Ley T.J. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004; 21 (4): 589-601. doi:10.1016/j.immuni.2004.09.002Trzonkowski P, Szmit E., Mysliwska J., Dobyszuk A., Myśliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol. 2004; 112 (3): 258-267. doi:10.1016/j.clim.2004.04.003Trzonkowski P, Szmit E., Mysliwska J., Dobyszuk A., Myśliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol. 2004; 112 (3): 258-267. doi:10.1016/j.clim.2004.04.003Rueda C.M., Jackson C.M., Chougnet C.A. Regulatory T-cell-mediated suppression of conventional T-cells and dendritic cells by different cAMP intracellular pathways. Front Immunol. 2016; 7: 216. doi:10.3389/fimmu.2016.00216Rueda C.M., Jackson C.M., Chougnet C.A. Regulatory T-cell-mediated suppression of conventional T-cells and dendritic cells by different cAMP intracellular pathways. Front Immunol. 2016; 7: 216. doi:10.3389/fimmu.2016.00216Kobie J.J., Shah PR., Yang L., Rebhahn J.A., Fowell D.J., Mosmann T.R. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol. 2006; 177 (10): 6780-6786. doi:10.4049/jimmunol.177.10.6780Kobie J.J., Shah PR., Yang L., Rebhahn J.A., Fowell D.J., Mosmann T.R. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol. 2006; 177 (10): 6780-6786. doi:10.4049/jimmunol.177.10.6780Takenaka M.C., Robson S., Quintana F.J. Regulation of the T cell response by CD39. Trends Immunol. 2016; 37 (7): 427-439. doi:10.1016/j.it.2016.04.009Takenaka M.C., Robson S., Quintana F.J. Regulation of the T cell response by CD39. Trends Immunol. 2016; 37 (7): 427-439. doi:10.1016/j.it.2016.04.009Chen G.Y, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10 (12): 826-837. doi:10.1038/nri2873Chen G.Y, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10 (12): 826-837. doi:10.1038/nri2873Cauwels A., Rogge E., Vandendriessche B., Shiva S., Brouckaert P Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis. 2014; 5: e1102. doi:10.1038/cddis.2014.70Cauwels A., Rogge E., Vandendriessche B., Shiva S., Brouckaert P Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis. 2014; 5: e1102. doi:10.1038/cddis.2014.70Trabanelli S., Ocadhkova D., Gulinelli S., Curti A., Salvestrini V., Vieira R.P., Idzko M., Di Virgilio F., Ferrari D., Lemoli R.M. Extracellular ATP exerts opposite effects on activated and regulatory CD4+ T cells via purinergic P2 receptor activation. J Immunol. 2012; 189 (3): 1303-1310. doi:10.4049/jimmunol.1103800Trabanelli S., Ocadhkova D., Gulinelli S., Curti A., Salvestrini V., Vieira R.P., Idzko M., Di Virgilio F., Ferrari D., Lemoli R.M. Extracellular ATP exerts opposite effects on activated and regulatory CD4+ T cells via purinergic P2 receptor activation. J Immunol. 2012; 189 (3): 1303-1310. doi:10.4049/jimmunol.1103800Pandiyan P, Zheng L., Ishihara S., Reed J., Lenardo M.J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature Immunology. 2007; 8, 1353-1362. doi:10.1038/ni1536Pandiyan P, Zheng L., Ishihara S., Reed J., Lenardo M.J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature Immunology. 2007; 8, 1353-1362. doi:10.1038/ni1536Kearley J., Barker J.E., Robinson D.S., Lloyd C.M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+ CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med. 2005; 202 (11): 1539-1547. doi:10.1084/jem.20051166Kearley J., Barker J.E., Robinson D.S., Lloyd C.M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+ CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med. 2005; 202 (11): 1539-1547. doi:10.1084/jem.20051166Francisco 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; 206 (13): 3015-3029. doi:10.1084/jem.20090847Francisco 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; 206 (13): 3015-3029. doi:10.1084/jem.20090847Chen X., Fosco D., Kline D.E., Meng L., Nishi S., Savage P.A., Kline J. PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol. 2014; 44 (9): 2603-2616. doi:10.1002/eji.201344423Chen X., Fosco D., Kline D.E., Meng L., Nishi S., Savage P.A., Kline J. PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol. 2014; 44 (9): 2603-2616. doi:10.1002/eji.201344423Sakaguchi S. Control of immune responses by naturally arising CD4+regulatory T cells that express toll-like receptors. J. Exp. Med. 2003; 197 (4): 397-401. doi:10.1084/jem.20030012Sakaguchi S. Control of immune responses by naturally arising CD4+regulatory T cells that express toll-like receptors. J. Exp. Med. 2003; 197 (4): 397-401. doi:10.1084/jem.20030012Caramalho I., Lopes-Carvalho T., Ostler D., Zelenay S., Haury M., Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med. 2003; 197 (4): 403-411. doi:10.1084/jem.20021633Caramalho I., Lopes-Carvalho T., Ostler D., Zelenay S., Haury M., Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med. 2003; 197 (4): 403-411. doi:10.1084/jem.20021633Murphy T.J., Ni Choileain N., Zang Y., Mannick J.A., Lederer J.A. CD4+CD25+ regulatory T cells control innate immune reactivity after injury. Immunol. 2005; 174 (5): 29572963. doi:10.4049/jimmunol.174.5.2957Murphy T.J., Ni Choileain N., Zang Y., Mannick J.A., Lederer J.A. CD4+CD25+ regulatory T cells control innate immune reactivity after injury. Immunol. 2005; 174 (5): 29572963. doi:10.4049/jimmunol.174.5.2957Hanschen M., Tajima G., O'Leary F., Ikeda K., Lederer J.A. Injury induces early activation of T-cell receptor signaling pathways in CD4+ regulatory T cells. Shock 2011; 35 (3): 252257. doi:10.1097/SHK.0b013e3181f489c5Hanschen M., Tajima G., O'Leary F., Ikeda K., Lederer J.A. Injury induces early activation of T-cell receptor signaling pathways in CD4+ regulatory T cells. Shock 2011; 35 (3): 252257. doi:10.1097/SHK.0b013e3181f489c5Choileain N.N., MacConmara M., Zang Y, Murphy T.J., Mannick J.A., Lederer J.A. Enhanced regulatory T cell activity is an element of the host response to injury. J Immunol. 2006; 176 (1): 225-236. doi:10.4049/jimmunol.176.1.225Choileain N.N., MacConmara M., Zang Y, Murphy T.J., Mannick J.A., Lederer J.A. Enhanced regulatory T cell activity is an element of the host response to injury. J Immunol. 2006; 176 (1): 225-236. doi:10.4049/jimmunol.176.1.225MacConmara M.P., Tajima G., O'Leary F., Delisle A.J., McKenna A.M., Stallwood C.G., Mannick J.A., Lederer J. A. Regulatory T cells suppress antigen-driven CD4 T cell reactivity following injury. J Leukoc Biol. 2011; 89 (1): 137147. doi:10.1189/jlb.0210082MacConmara M.P., Tajima G., O'Leary F., Delisle A.J., McKenna A.M., Stallwood C.G., Mannick J.A., Lederer J. A. Regulatory T cells suppress antigen-driven CD4 T cell reactivity following injury. J Leukoc Biol. 2011; 89 (1): 137147. doi:10.1189/jlb.0210082Heuer J.G., Zhang T., Zhao J., Ding C., Cramer M., Justen K. L., Vonderfecht S.L., Na S. Adoptive transfer ofin vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol. 2005; 174 (11): 7141-7146. doi: 10.4049/jimmunol.174.11.714Heuer J.G., Zhang T., Zhao J., Ding C., Cramer M., Justen K. L., Vonderfecht S.L., Na S. Adoptive transfer ofin vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol. 2005; 174 (11): 7141-7146. doi: 10.4049/jimmunol.174.11.714Hein F., Massin F., Cravoisy-Popovic A., Barraud D., Levy B., Bollaert P.E., Gibot S. The relationship between CD4+CD25+CD127- regulatory T cells and inflammatory response and outcome during shock states. Crit Care. 2010; 14 (1): R19. doi:10.1186/cc8876Hein F., Massin F., Cravoisy-Popovic A., Barraud D., Levy B., Bollaert P.E., Gibot S. The relationship between CD4+CD25+CD127- regulatory T cells and inflammatory response and outcome during shock states. Crit Care. 2010; 14 (1): R19. doi:10.1186/cc8876Monneret G., Debard A.L., Venet F., Bohe J., Hequet O., Bienvenu J., Lepape A. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med. 2003; 31 (7): 2068-2071. doi:10.1097/01.CCM.0000069345.78884.0FMonneret G., Debard A.L., Venet F., Bohe J., Hequet O., Bienvenu J., Lepape A. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med. 2003; 31 (7): 2068-2071. doi:10.1097/01.CCM.0000069345.78884.0FVenet F., Pachot A., Debard A.L., Bohe J., Bienvenu J., Lepape A., Monneret G. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit Care Med. 2004; 32 (11): 2329-2331. doi:10.1097/01.CCM.0000145999.42971.4BVenet F., Pachot A., Debard A.L., Bohe J., Bienvenu J., Lepape A., Monneret G. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit Care Med. 2004; 32 (11): 2329-2331. doi:10.1097/01.CCM.0000145999.42971.4BHuang H., Xu R., Lin F., Bao C., Wang S., Ji C., Li K., Jin L., Mu J., Wang Y, Li L., Sun L., Xu B., Zhang Z., Wang F.S. High circulating CD39+ regulatory T cells predict poor survival for sepsis patients. Int J Infect Dis. 2015; 30: 57-63. doi:10.1016/j.ijid.2014.11.006Huang H., Xu R., Lin F., Bao C., Wang S., Ji C., Li K., Jin L., Mu J., Wang Y, Li L., Sun L., Xu B., Zhang Z., Wang F.S. High circulating CD39+ regulatory T cells predict poor survival for sepsis patients. Int J Infect Dis. 2015; 30: 57-63. doi:10.1016/j.ijid.2014.11.006Leng F. Y, Liu J.L., Liu Z.J., Yin J.Y, Qu H.P. Increased proportion of CD4+CD25+Foxp3+ regulatory T cells during early-stage sepsis in ICU patients. Journal of Microbiology, Immunology and Infection. 2013; 46 (5): 338-344. doi:10.1016/j.jmii.2012.06.012Leng F. Y, Liu J.L., Liu Z.J., Yin J.Y, Qu H.P. Increased proportion of CD4+CD25+Foxp3+ regulatory T cells during early-stage sepsis in ICU patients. Journal of Microbiology, Immunology and Infection. 2013; 46 (5): 338-344. doi:10.1016/j.jmii.2012.06.012MacConmara M.P., Maung A.A., Fujimi S., MacConmara M.P., Maung A.A., Fujimi S., McKenna A.M., Delisle A., Lapchak P.H., Rogers S., Lederer J.A., Mannick J.A. Increased CD4+ CD25+ T regulatory cell activity in trauma patients depresses protective Th1 immunity. Ann Surg. 2006; 244 (4): 514-523. doi:10.1097/01.sla.0000239031.06906.1fMacConmara M.P., Maung A.A., Fujimi S., MacConmara M.P., Maung A.A., Fujimi S., McKenna A.M., Delisle A., Lapchak P.H., Rogers S., Lederer J.A., Mannick J.A. Increased CD4+ CD25+ T regulatory cell activity in trauma patients depresses protective Th1 immunity. Ann Surg. 2006; 244 (4): 514-523. doi:10.1097/01.sla.0000239031.06906.1fKuhlhorn F., Rath M., Schmoeckel K., Cziupka K., Nguyen H.H., Hildebrandt P., Hunig T., Sparwasser T., Huehn J., Potschke C., Broker B.M. Foxp3+ regulatory T cells are required for recovery from severe sepsis. PLoS One. 2013; 8 (5): e65109. doi:10.1371/journal.pone.0065109Kuhlhorn F., Rath M., Schmoeckel K., Cziupka K., Nguyen H.H., Hildebrandt P., Hunig T., Sparwasser T., Huehn J., Potschke C., Broker B.M. Foxp3+ regulatory T cells are required for recovery from severe sepsis. PLoS One. 2013; 8 (5): e65109. doi:10.1371/journal.pone.0065109Deaglio S., Dwyer K.M., Gao W., Friedman D., Usheva A., Erat A., Chen J.F., Enjyoji K., Linden J., Oukka M., Kuchroo V.K., Strom T.B., Robson S.C. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204 (6): 1257-1265. doi:10.1084/jem.20062512Deaglio S., Dwyer K.M., Gao W., Friedman D., Usheva A., Erat A., Chen J.F., Enjyoji K., Linden J., Oukka M., Kuchroo V.K., Strom T.B., Robson S.C. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204 (6): 1257-1265. doi:10.1084/jem.20062512Chen K., Zhou Q.X., Shan H.W., Li W.F., Lin Z.F. Prognostic value of CD4+ CD25+ Tregs as a valuable biomarker for patients with sepsis in ICU. World J Emerg Med. 2015; 6 (1): 40-43. doi:10.5847/wjem.j.1920-8642.2015.01.007Chen K., Zhou Q.X., Shan H.W., Li W.F., Lin Z.F. Prognostic value of CD4+ CD25+ Tregs as a valuable biomarker for patients with sepsis in ICU. World J Emerg Med. 2015; 6 (1): 40-43. doi:10.5847/wjem.j.1920-8642.2015.01.007

The authors declare that there are no conflicts of interest present.