actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2023-8.3.5actabiomedica-4207Research ArticleБИОХИМИЯBIOCHEMISTRYМаркеры Th1-поляризованных клеток Th17 (обзор литературы)Markers of Th1 polarized Th17 cells (literature review)https://orcid.org/0000-0002-2173-2724КуклинаЕ. М.KuklinaE. M.

Куклина Елена Михайловна – доктор биологических  наук, ведущий научный сотрудник лаборатории  иммунорегуляции

 614081, г. Пермь, ул. Голева, 13, Россия 

Elena M. Kuklina – Dr. Sc, (Biol.), Leading Research Officer at the Laboratory of Immunoregulation

Goleva str. 13, Perm 614081, Russian Federation 

ibis_07@mail.ruhttps://orcid.org/0000-0002-9891-0509ГлебездинаН. С.GlebezdinaN. S.

Глебездина Наталья Сергеевна – кандидат биологических наук, младший научный сотрудник лаборатории иммунорегуляции

 614081, г. Пермь, ул. Голева, 13, Россия 

Natalya S. Glebezdina – Cand. Sc. (Biol.), Junior Research Officer at the Laboratory of Immunoregulation 

Goleva str. 13, Perm 614081, Russian Federation 

glebezdina_n@mail.ruИнститут экологии и генетики микроорганизмов Уральского отделения Российской академии наук – филиал ФГБУН Пермского федерального исследовательского центра УрО РАНInstitute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences – Branch of the Perm Federal Research Center UB RAS202311072023835562Copyright © Куклина Е.М., Глебездина Н.С., 20232023Куклина Е.М., Глебездина Н.С.Kuklina E.M., Glebezdina N.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/4207

Т-хелперы (Th, T helpers), продуцирующие IL-17 (Th17), обладают высокой пластичностью и под влиянием внешних условий способны редифференцироваться в клетки с другим фенотипом, прежде всего в Th1-лимфоциты, формируя популяцию, сочетающую в себе характеристики как Th17, так и Th1 и обладающую высоким провоспалительным потенциалом, а также уникальной способностью преодолевать гистогематические барьеры. Именно этим клеткам в настоящее время отводится ключевая роль в патогенезе многих воспалительных заболеваний, включая и аутоиммунные: в инфильтратах воспалённых тканей на их долю приходится до половины присутствующих там лимфоцитов. В работе обсуждаются причины повышенной пластичности клеток Th17 в сравнении с основными Т-хелперными популяциями (Th1 и Th2) и подробно рассматриваются механизмы формирования IFNγ-продуцирующих Th17 с учётом не только редифференцировки зрелых Th17, но и возможных альтернативных путей, в частности редифференцировки клеток Th1 или непосредственной дифференцировки наивных CD4+Тлимфоцитов в клетки с промежуточным Th1/Th17-фенотипом. Также обсуждаются основные индукторы дифференцировки IFNγ-продуцирующих клеток Th17 и обратимость этого процесса. Особое внимание в обзоре уделено способам идентификации Th1-поляризованных клеток Th17: эта популяция неоднородна, и её размер существенно зависит от типа маркеров, используемых для характеристики данных клеток – Th1/Th17-ассоциированных транскрипционных факторов, ключевых цитокинов, а также хемокиновых рецепторов и других мембранных молекул. Как следствие, данные в работах по этой проблеме плохо сопоставимы друг с другом. Унификация подходов к выявлению популяции Th1-подобных Th17 позволит решить эту проблему и даст возможность использовать оценку размера и активности такой популяции в качестве диагностических или прогностических маркеров.

T helpers (Th) producing IL-17 (Th17) have high plasticity and under the influence of external conditions are able to redifferentiate into cells with a different phenotype, primarily in Th1-lymphocytes, forming a population that combines the characteristics of both Th17 and Th1 and has a high pro-inflammatory potential, as well as a unique ability to overcome histohematic barriers. These cells are currently assigned a key role in the pathogenesis of many inflammatory diseases, including autoimmune ones: they account for up to half of the lymphocytes present in infiltrates of inflamed tissues. The paper discusses the reasons for the increased plasticity of Th17 cells in comparison with the main T helper populations (Th1 and Th2) and considers in detail the mechanisms of formation of IFNγ producing Th17, taking into account not only the redifferentiation of mature Th17, but also possible alternative pathways, in particular, Th1 cell redifferentiation or naive CD4+T lymphocytes direct differentiation into cells with an intermediate Th1/Th17 phenotype. The main inducers of differentiation of IFNγ producing Th17 cells and the reversibility of this process are also discussed. Particular attention is paid to the methods for identifying Th1 polarized Th17 cells: this population is heterogeneous, and its size significantly depends on the type of markers used to characterize these cells – Th1/Th17-associated transcription factors, key cytokines, as well as chemokine receptors and other membrane molecules. As a result, the data in the works on this problem are poorly comparable with each other. The unification of approaches to identifying a population of Th1 like Th17 cells will solve this problem and make it possible to use an assessment of the size and activity of such a population as diagnostic or prognostic markers.

Th17Th1пластичностьредифференцировкаTh17.1ex-Th17Th17Th1plasticityredifferentiationTh17.1ex-Th17Исследование выполнено при финансовой поддержке Российского научного фонда и Пермского края в рамках научного проекта № 22-25-20121.ReferencesAhern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010; 33(2): 279-288. doi: 10.1016/j.immuni.2010.08.010Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010; 33(2): 279-288. doi: 10.1016/j.immuni.2010.08.010Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011; 12: 255-263. doi: 10.1038/ni.1993Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011; 12: 255-263. doi: 10.1038/ni.1993Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009; 30(1): 92-107. doi: 10.1016/j.immuni.2008.11.005Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009; 30(1): 92-107. doi: 10.1016/j.immuni.2008.11.005Lexberg MH, Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, et al. IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol. 2010; 40(11): 3017-3027. doi: 10.1002/eji.201040539Lexberg MH, Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, et al. IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol. 2010; 40(11): 3017-3027. doi: 10.1002/eji.201040539Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007; 204(8): 1849-1861. doi: 10.1084/jem.20070663Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007; 204(8): 1849-1861. doi: 10.1084/jem.20070663Maggi L, Santarlasci V, Capone M, Rossi MC, Querci V, Mazzoni A, et al. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur J Immunol. 2012; 42(12): 3180-3188. doi: 10.1002/eji.201242648Maggi L, Santarlasci V, Capone M, Rossi MC, Querci V, Mazzoni A, et al. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur J Immunol. 2012; 42(12): 3180-3188. doi: 10.1002/eji.201242648Quirant-Sanchez B, Presas-Rodriguez S, Mansilla MJ, Teniente-Serra A, Hervas-Garcia JV, Brieva L, et al. Th1Th17CM lymphocyte subpopulation as a predictive biomarker of disease activity in multiple sclerosis patients under dimethyl fumarate or fingolimod treatment. Mediators Inflamm. 2019; 2019: 8147803. doi: 10.1155/2019/8147803Quirant-Sanchez B, Presas-Rodriguez S, Mansilla MJ, Teniente-Serra A, Hervas-Garcia JV, Brieva L, et al. Th1Th17CM lymphocyte subpopulation as a predictive biomarker of disease activity in multiple sclerosis patients under dimethyl fumarate or fingolimod treatment. Mediators Inflamm. 2019; 2019: 8147803. doi: 10.1155/2019/8147803Dhaeze T, Tremblay L, Lachance C, Peelen E, Zandee S, Grasmuck C, et al. CD70 defines a subset of proinflammatory and CNS-pathogenic TH1/TH17 lymphocytes and is overexpressed in multiple sclerosis. Cell Mol Immunol. 2019; 16(7): 652-665. doi: 10.1038/s41423-018-0198-5Dhaeze T, Tremblay L, Lachance C, Peelen E, Zandee S, Grasmuck C, et al. CD70 defines a subset of proinflammatory and CNS-pathogenic TH1/TH17 lymphocytes and is overexpressed in multiple sclerosis. Cell Mol Immunol. 2019; 16(7): 652-665. doi: 10.1038/s41423-018-0198-5Duhen T, Campbell DJ. IL-1β promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol. 2014; 193(1): 120-129. doi: 10.4049/jimmunol.1302734Duhen T, Campbell DJ. IL-1β promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol. 2014; 193(1): 120-129. doi: 10.4049/jimmunol.1302734Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA. 2010; 107(33): 14751-14756. doi: 10.1073/pnas.1003852107Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA. 2010; 107(33): 14751-14756. doi: 10.1073/pnas.1003852107Dhodapkar КМ, Barbuto S, Matthews P, Kukreja A, Mazumder A, Vesole D, et al. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood. 2008; 112(7): 2878-2885. doi: 10.1182/blood-2008-03-143222Dhodapkar КМ, Barbuto S, Matthews P, Kukreja A, Mazumder A, Vesole D, et al. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood. 2008; 112(7): 2878-2885. doi: 10.1182/blood-2008-03-143222Ramesh R, Kozhaya L, McKevitt K, Djuretic IM, Carlson TJ, Quintero MA, et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med. 2014; 211(1): 89-104. doi: 10.1084/jem.20130301Ramesh R, Kozhaya L, McKevitt K, Djuretic IM, Carlson TJ, Quintero MA, et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med. 2014; 211(1): 89-104. doi: 10.1084/jem.20130301Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, et al. IFN-γ-producing T-helper 17.1 cells are increased in sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med. 2016; 193(11): 1281-1291. doi: 10.1164/rccm.201507-1499OCRamstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, et al. IFN-γ-producing T-helper 17.1 cells are increased in sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med. 2016; 193(11): 1281-1291. doi: 10.1164/rccm.201507-1499OCDankers W, den Braanker H, Paulissen SMJ, van Hamburg JP, Davelaar N, Colin EM, et al. The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner. Arthritis Res Ther. 2021; 23(1): 157. doi: 10.1186/s13075-021-02532-9Dankers W, den Braanker H, Paulissen SMJ, van Hamburg JP, Davelaar N, Colin EM, et al. The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner. Arthritis Res Ther. 2021; 23(1): 157. doi: 10.1186/s13075-021-02532-9Nishihara H, Soldati S, Mossu A, Rosito M, Rudolph H, Muller WA, et al. Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro. Fluids Barriers CNS. 2020; 17(1): 3. doi: 10.1186/s12987-019-0165-2Nishihara H, Soldati S, Mossu A, Rosito M, Rudolph H, Muller WA, et al. Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro. Fluids Barriers CNS. 2020; 17(1): 3. doi: 10.1186/s12987-019-0165-2Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007; 8(6): 639-646. doi: 10.1038/ni1467Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007; 8(6): 639-646. doi: 10.1038/ni1467Belpaire А, van Geel N, Speeckaert R. From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target? Front Immunol. 2022; 13: 932265. doi: 10.3389/fimmu.2022.932265Belpaire А, van Geel N, Speeckaert R. From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target? Front Immunol. 2022; 13: 932265. doi: 10.3389/fimmu.2022.932265McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009; 10(3): 314-324. doi: 10.1038/ni.1698McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009; 10(3): 314-324. doi: 10.1038/ni.1698Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010; 140(6): 845-858. doi: 10.1016/j.cell.2010.02.021Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010; 140(6): 845-858. doi: 10.1016/j.cell.2010.02.021Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity. 2010; 32(5): 616-627. doi: 10.1016/j.immuni.2010.04.016Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity. 2010; 32(5): 616-627. doi: 10.1016/j.immuni.2010.04.016Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007; 204(12): 2803-2812. doi: 10.1084/jem.20071397Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007; 204(12): 2803-2812. doi: 10.1084/jem.20071397Leipe J, Pirronello F, Schoolze-Koops H, Skapenko A. Increased plasticity of non-classic Th1 cells toward the Th17 phenotype. Mod Reumatol. 2020; 30(5): 930-936. doi: 10.1080/14397595.2019.1667473Leipe J, Pirronello F, Schoolze-Koops H, Skapenko A. Increased plasticity of non-classic Th1 cells toward the Th17 phenotype. Mod Reumatol. 2020; 30(5): 930-936. doi: 10.1080/14397595.2019.1667473Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Joanne Konkel J, et al. Generation of pathogenic Th17 cells in the absence of TGF-β signaling. Nature. 2010; 467(7318): 967-971. doi: 10.1038/nature09447Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Joanne Konkel J, et al. Generation of pathogenic Th17 cells in the absence of TGF-β signaling. Nature. 2010; 467(7318): 967-971. doi: 10.1038/nature09447Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009; 66(3): 390-402. doi: 10.1002/ana.21748Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009; 66(3): 390-402. doi: 10.1002/ana.21748Duhen R, Glatigny S, Arbelaez CA, Blair TC, Oukka M, Bettelli E. Cutting edge: The pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet. J Immunol. 2013; 190(9): 4478-4482. doi: 10.4049/jimmunol.1203172Duhen R, Glatigny S, Arbelaez CA, Blair TC, Oukka M, Bettelli E. Cutting edge: The pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet. J Immunol. 2013; 190(9): 4478-4482. doi: 10.4049/jimmunol.1203172Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, et al. Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015; 349(6248): 606-613. doi: 10.1126/science.aaa4282Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, et al. Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015; 349(6248): 606-613. doi: 10.1126/science.aaa4282Mazzoni A, Maggi L, Siracusa F, Ramazzotti M, Rossi MC, Santarlasci V, et al. Eomes controls the development of Th17‐derived (non-classic) Th1 cells during chronic inflammation. Eur J Immunol. 2019; 49(1): 79-95. doi: 10.1002/eji.201847677Mazzoni A, Maggi L, Siracusa F, Ramazzotti M, Rossi MC, Santarlasci V, et al. Eomes controls the development of Th17‐derived (non-classic) Th1 cells during chronic inflammation. Eur J Immunol. 2019; 49(1): 79-95. doi: 10.1002/eji.201847677Li P, Spolski R, Liao W, Leonard WJ. Complex interactions of transcription factors in mediating cytokine biology in T cells. Immunol Rev. 2014; 261(1): 141-156. doi: 10.1111/imr.12199Li P, Spolski R, Liao W, Leonard WJ. Complex interactions of transcription factors in mediating cytokine biology in T cells. Immunol Rev. 2014; 261(1): 141-156. doi: 10.1111/imr.12199Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest, 2011; 121(11): 4503-4515. doi: 10.1172/JCI57456Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest, 2011; 121(11): 4503-4515. doi: 10.1172/JCI57456Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007; 26(3): 371-381. doi: 10.1016/j.immuni.2007.02.009Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007; 26(3): 371-381. doi: 10.1016/j.immuni.2007.02.009Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, et al. A validated regulatory network for Th17 cell specification. Cell. 2012; 151(2): 289-303. doi: 10.1016/j.cell.2012.09.016Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, et al. A validated regulatory network for Th17 cell specification. Cell. 2012; 151(2): 289-303. doi: 10.1016/j.cell.2012.09.016Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL‐12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000; 13(5): 715-725. doi: 10.1016/s1074-7613(00)00070-4Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL‐12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000; 13(5): 715-725. doi: 10.1016/s1074-7613(00)00070-4Tait Wojno ED, Hunter CA, Stumhofer JS. The immunobiology of the interleukin-12 family: Room for discovery. Immunity. 2019; 50(4): 851-870. doi: 10.1016/j.immuni.2019.03.011Tait Wojno ED, Hunter CA, Stumhofer JS. The immunobiology of the interleukin-12 family: Room for discovery. Immunity. 2019; 50(4): 851-870. doi: 10.1016/j.immuni.2019.03.011Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature. 2013; 496(7446): 513-517. doi: 10.1038/nature11984Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature. 2013; 496(7446): 513-517. doi: 10.1038/nature11984Yang BH, Floess S, Hagemann S, Deyneko IV, Groebe L, Pezoldt J, et al. Development of a unique epigenetic signature during in vivo Th17 differentiation. Nucleic Acids Res. 2015; 43(3): 1537-1548. doi: 10.1093/nar/gkv014Yang BH, Floess S, Hagemann S, Deyneko IV, Groebe L, Pezoldt J, et al. Development of a unique epigenetic signature during in vivo Th17 differentiation. Nucleic Acids Res. 2015; 43(3): 1537-1548. doi: 10.1093/nar/gkv014Mazzoni A, Santarlasci V, Maggi L, Capone M, Rossi MC, Querci V, et al. Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclassic Th1 cells. J Immunol. 2015; 194(7): 3116-3126. doi: 10.4049/jimmunol.1401303Mazzoni A, Santarlasci V, Maggi L, Capone M, Rossi MC, Querci V, et al. Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclassic Th1 cells. J Immunol. 2015; 194(7): 3116-3126. doi: 10.4049/jimmunol.1401303Cohen CJ, Crome SQ, MacDonald KG, Dai EL, Mager DL, Levings MK. Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol. 2011; 187(11): 5615-5626. doi: 10.4049/jimmunol.1101058Cohen CJ, Crome SQ, MacDonald KG, Dai EL, Mager DL, Levings MK. Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol. 2011; 187(11): 5615-5626. doi: 10.4049/jimmunol.1101058Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, Turner SP, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med. 2009; 206(3): 525-534. doi: 10.1084/jem.20081712Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, Turner SP, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med. 2009; 206(3): 525-534. doi: 10.1084/jem.20081712

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