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Research Progress of Th17/Treg Cells and Their Transcription Factors in Autoimmune Diseases
American Journal of Clinical and Experimental Medicine
Volume 7, Issue 4, July 2019, Pages: 83-92
Received: Jul. 9, 2019; Published: Sep. 27, 2019
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Zhenjiang Hou, Institute of Thyroid Diseases Affiliated to Cangzhou Medical College, Cangzhou Thyroid Disease Engineering Technology Research Center, Cangzhou, China
Zhaoxin Mu, Institute of Thyroid Diseases Affiliated to Cangzhou Medical College, Cangzhou Thyroid Disease Engineering Technology Research Center, Cangzhou, China
Cuicui Wang, Department of Medical Technology Laboratory, Cangzhou Medical College, Cangzhou, China
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Helper T cell 17 (Th17) being a new cell subset of CD4+T in the body, which is different from Th1 and Th2 cells, have independent mechanisms of differentiation and developmental regulation. Th17 cells mainly secrete various cytokines such as IL-17, IL-6 and TNF-α, which induce inflammation. Treg cells are T cells with high expression of CD25 differentiated by T cells under the action of certain cytokines, namely CD4+CD25+(hi) Foxp3+T cells, which can regulate the immune response mediated by effector cells and are an important line of defense for human autoimmune. Therefore, Treg cells play an important role in maintaining immune tolerance of the body. As an important subset of T cells, Treg cells have an inhibitory effect on inflammation. Its working principle is to selectively inhibit autoreactive T cells and effector T cells so as to maintain the body's immune balance, and normal quantity and function help the immune system to its antigen stimulation, establishing a good state of tolerance. The expression of Treg cells increased, can avoid the occurrence of autoimmune diseases. Treg cells inhibit the differentiation of Th17 cells by down-regulating the expression of IL-23 and IL-17 or by its specific transcription factor Foxp3; similarly, inhibition of Th17 cell production can promote the development of Treg cells. Both Th17 and Treg cells are functionally inhibited. Th17 cells promote inflammatory reaction, and Treg cells suppress immune reaction. Numerous cytokines are involved in regulation. For example, IL-6 and IL-21 can inhibit Foxp3 and promote the expression of RORγt, thereby inhibiting Treg cells and inducing the differentiation of Th17 cells. In the absence of IL-6 and other pro-inflammatory factors, TGF-β enhances the inhibitory effect of Foxp3 on RORγt and promotes the growth and development of Treg cells. The anti-inflammatory factor IL-10 also induces Treg cells to inhibit the reaction of Th17 cells. The effects of Treg and Th17 cells are normally in a dynamic equilibrium. Once the balance is imbalanced, autoimmune diseases will occur. This article reviews the differentiation, function and research progress of Th17/Treg cells in autoimmune diseases.
Helper T 17 Cell, Regulatory T Cell, Retinoidrelated Orphan Receptors -γt, Forkhead/Winged, Helix Transcription Factor 3, Autoimmune Diseases
To cite this article
Zhenjiang Hou, Zhaoxin Mu, Cuicui Wang, Research Progress of Th17/Treg Cells and Their Transcription Factors in Autoimmune Diseases, American Journal of Clinical and Experimental Medicine. Vol. 7, No. 4, 2019, pp. 83-92. doi: 10.11648/j.ajcem.20190704.12
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Shabgah AG, Fattahi E, Shahneh FZ. Interleukin-17 in human inflammatory diseases. Postepy Dermatol Alergol, 2014, vol. 31, pp. 256-261.
Kleinewietfeld M, Hafler DA. Regulatory T cells in autoimmune neuroinflammation [J]. Immunol Rev. 2014, vol. 259, pp. 231-244.
Ma A, Yang Y, Wang Q, et al. Anti‑inflammatory effects of oxymatrine on rheumatoid arthritis in rats via regulating the imb-alance between Treg and Th17 cells [J]. Mol Med Rep. 2017, vol. 15, pp. 3615-3622.
Hou X, Song J, Su J, et al. CD4(+)Foxp3(+) Tregs protect against innate immune cell-mediated fulminant hepatitis in mice [J]. Mol Immunol. 2015, vol. 63, pp. 420-427.
Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation [J]. Nat Rev Drug Discov, 2012, vol. 11, pp. 763-776.
Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17cells in the absence of TGF-β signalling [J]. Nature, 2010, vol. 467, pp. 967-971.
Annunziato F, Cosmi L, Liotta F, et al. Type 17 T helper cells-origins, features and possible roles in rheumatic disease [J]. Nat Rev Rheumatol, 2009, vol. 5, pp. 325-331.
Mangodt TC, Van Herck MA, Nullens S, et al. The role of Th17 and Treg responses in the pathogenesis of RSV infection [J]. Pediatr Res, 2015, vol. 78, pp. 483-491.
Ballke C, Gran E, Baekkevold ES, et al. Characterization of Regulatory T-Cell Markers in CD4+ T Cells of the Upper Airway Mucosa [J]. PLoSOne, 2016, vol. 11, pp. e0148826
Abd Al Samid M, Chaudhary B, Khaled YS, et al. Combining FoxP3 and Helios with GARP/LAP markers can identify expan-ded Treg subsets in cancer patients [J]. Oncotarget, 2016, vol. 7, pp. 14083-14094.
Pandiyan P, Zhu JF. Origin and functions of pro-inflammatory cytokine producing Foxp3(+) regulatory T cells [J]. Cytokine, 2015, vol. 76, pp. 13-24.
Hall BM, Verma ND, Tran GT, et al. Distinct regulatory CD4+T cell subsets; differences between naïve and antigen specific T regulatory cells [J]. Curr Opin Immunol, 2011, vol. 23, pp. 641-647.
Kugyelka R, Kohl Z, Olasz K, et al. Enigma of IL-17 and Th17 cells in rheumatoid arthritis and in autoimmune animal mod-els ofarthritis [J]. Mediators Inflammation, 2016, pp. 6145810.
van Hamburg JP, Asmawidjaja PS, Davelaar N, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthri-tis are potent inducers of matrix metalloproteinases and proin amatory cytokines upon synovial fbroblast interaction, including autocrine interleukin-17A production [J]. Arthritis Rheumatism, 2011, vol. 63, pp. 73-83.
Wang T, Sun X, Zhao J, et al. Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood [J]. Ann Rheum Dis, 2015, vol. 74, pp. 1293-1301.
Lee YH, Bae SC. Associations between circulating IL-17 levels and rheumatoid arthritis and between IL-17 gene polymor-phisms and disease susceptibility: a meta-analysis [J]. Postgrad Med J, 2017, vol. 93, pp. 465-471.
Wei M. Efficacy and safety of monoclonal antibodies targeting interleukin-17 pathway for inflammatory arthritis: a meta-analysis of randomized controlled clinical trials [J]. Drug Des Devel Ther, 2016, vol. 10, pp. 2771-2777.
Attridge K, Wang CJ, Wardzinski L, et al. IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis [J]. Blood, 2012, vol. 119, pp. 4656-4664.
Miyara M, Gorochov G, Ehrenstein M, et al. Human FoxP3 regulatory T cells in systemic autoimmune diseases [J]. Autoimm-un Rev, 2011, vol. 10, pp. 744-755.
Walter GJ, Fleskens V, Frederiksen KS, et al. Phenotypic, Functional, and Gene Expression Profiling of Peripheral CD45RA+and CD45RO+CD4+CD25+CD127 (low) Treg Cells in Patients With Chronic Rheumatoid Arthritis [J]. Arthritis Rheumatol, 2016, vol. 68, pp. 103-116.
Flores-Borja F, Bosma A, Ng D, Reddy V, et al. CD19+CD24hiCD38hiB cells maintain regulatory T cells while limiting TH1 and TH17 differentiation [J]. Sci Transl Med, 2013, 5 (173): 2013, vol. 5, pp. 173ra23.
Ma L, Liu B, Jiang Z, et al. Reduced numbers of regulatory B cells are negatively correlated with disease activity in patients with new-onset rheumatoid arthritis [J]. Clin Rheumatol, 2014, vol. 33, pp. 187-195.
Daien CI, Gailhac S, Mura T, et al. Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity [J]. Arthritis Rheumatol, 2014, vol. 66, pp. 2037-2046.
Cui D, Zhang L, Chen J, et al. Changes in regulatory B cells and their relationship with rheumatoid arthritis disease activity [J]. Clin Exp Med, 2015, vol. 15, pp. 285-292.
Kim J, Lee HJ, Yoo IS, et al. Regulatory B cells are inversely associated with disease activity in rheumatoid arthritis [J]. Yon-sei Med J, 2014, vol. 55, pp. 1354-1358.
Kawashiri SY, Kawakami A, Okada A, et al. CD4+CD25 (high) CD127 (low/-) Treg cell frequency from peripheral blood cor-relates with disease activity in patients with rheumatoid arthritis [J]. J Rheumatol, 2011, vol. 38 pp. 2517-2521.
Möttönen M, Heikkinen J, Mustonen L, et al. CD4+CD25+T cell with the phenotypic and functional characteristics of regul-atory T cells are enriched in the synovial fluid of patientswith rheumatoid arthritis [J]. Clin Exp Immunol, 2005, vol. 140 pp. 360-367.
Astry B, Venkatesha SH, Moudgil KD. Involvement of the IL-23/IL-17 axis and the Th17/Treg balance in the pathogenesisand control of autoimmune arthritis [J]. Cytokine. 2015, vol. 74. pp. 54-61.
Boissier MC, Assier E, Biton J, et al. Regulatory T cells (Treg) in rheumatoid arthritis [J]. Joint Bone Spine, 2009, vol. 76. pp. 10-14.
Thiolat A, Denys A, Petit M, et al. Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice [J]. Cytokine, 2014, vol. 69. pp. 87-93.
Wang W, Shao S, Jiao Z, et al. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis [J]. Rheumatol Int, 2012, vol. 32. pp. 887-893.
Nie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis [J]. Nat Med, 2013, vol. 19. pp. 322-328.
Liang H, Yi L, Wang X, et al. Interleukin-17 facilitates the immune suppressor capacity of high- grade glioma-derived CD4(+)CD25(+)Foxp3(+) T cells via releasing transforming growth factor beta [J]. Scand J Immunol, 2014, vol. 80. pp. 144-150.
Wang X, Wang W, Xu J, et al. All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF- β [J]. BMC Immunol, 2015, vol. 16. pp. 17.
Hovhannisyan Z, Treatman J, Littman DR, et al. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases [J]. Gastroenterology, 2011, vol. 140. pp. 957-965.
Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells [J]. J Immunol, 2007, vol. 178. pp. 7849-7858.
Hsu HC, Yang PA, Wang J, et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice [J]. Nat Immunol, 2008, vol. 9. pp. 166-175.
Araújo JA, Mesquita D, de Melo Cruvinel W, et al. Th17 cells and CD4(+) multifunctional T cells in patients with systemic lupus erythematosus [J]. Rev Bras Reumatol, 2016, vol. 74. pp. 28-36.
An N, Chen Y, Wang C, et al. Chloroquine autophagic inhibition rebalances Th17/Treg-mediated immunity and ameliorates systemic lupus erythematosus [J]. Cell Physiol Biochem, 2017, vol. 44. pp. 412-422.
Talaat RM, Mohamed SF, Bassyouni IH, et al. Th1/Th2/Th17 /Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity [J]. Cytokine, 2015, vol. 72. pp. 146-153.
Zickert A, Amoudruz P, Sundstrm Y, et al. IL-17 and IL-23 in lupus nephritis-association to histopathology and response to treatment [J]. BMC Immunol, 2015, vol. 16. pp. 7.
Von Spee-Mayer C, Siegert E, Abdirama D, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus [J]. Ann Rheum Dis. 2016, vol. 75. pp 1407-1415.
Humrich JY, Morbach H, Undeutsch R, et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 depriva-tion amplifies murine lupus [J]. Proc Natl Acad Sci USA, 2010, vol. 107. pp. 204-209.
Lee HY, Hong YK, Yun HJ, et al. Altered frequency and migration capacity of CD+4 CD+25 regulatory T cells in systemic lupus erythematosus [J]. Rheumatol, 2008, vol. 47. pp. 789-794.
Gomez J, Prado C, Lopez P, et al. Conserved anti-proliferative effect and poor inhibition of TNF-α secretion by regulatory CD4 CD25 T cells in patients with systemic lupus erythematosus [J]. Clin Immunol, 2009, vol. 132. pp. 385-392.
Jia HY, Cheng GH. Expression and significance of Th17 cells and Treg cells and related cytokines in peripheral blood of patients with SLE [J]. Hebei Medicine, 2018, vol. 24. pp. 1277-1280.
Diani MAltomare G. T helper cell subsets in clinical manifestations of psoriasis [J]. J Immunol Res, 2016, pp. 7692024.
Adamopoulos IE, Suzuki E, Chao CC, et al. IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis [J]. Ann Rheum Dis, 2015, vol. 74. pp. 1284-1292.
Sakkas LI, Bogdanos DP, et al. Are psoriasis and psoriatic arthritis the same disease? The IL-23 /IL-17 axis data [J]. Auto-immun Rev, 2017, vol. 16. pp. 10-15.
Abji F, Pollock RA, Liang K, et al. Th17 gene expression in psoriatic arthritis synovial fluid and peripheral blood compared to osteoarthritis and cutaneous psoriasis [J]. Clin Exp Rheumatol, 2018, vol. 36. pp. 486-489.
Keijsers RR, Joosten I, Hendriks AG, et al. Balance of Treg versus T-effector cells during systemic treatment with adalimu-mab and topicaltreatment with calcipotriol-betamethasone dipropionate ointment. Exp Dermatol. 2015, vol. 24. pp. 65-67.
Zhang L, Li Y, Yang X, et al. Characterization of Th17 and FoxP3(+)Treg Cells in Paediatric Psoriasis Patients [J]. Scand J Immunol. 2016, vol. 83. pp. 174-180.
Van der Aar AM, Sibiryak DS, Bakdash G, et al. VitaminD3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells [J]. J Allergy Clin Im munol, 2011, vol. 127. pp. 1532-1540.
Correale J, Farez M, Razzitte G. Helminth infections associated with multiple sclerosis induce regulatory B cells [J]. AnnNeurol, 2008, vol. 64. pp. 187-199.
Knippenberg S, Peelen E, Smolders J, et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naïve/memory Breg ratio during a relapse but not in remission [J]. J Neuroimmunol, 2011 vol. 239. pp. 80-86.
Schubert RD, Hu Y, Kumar G, et al. IFN-β treatment requires B cells for efficacy in neuroauto immunity [J]. J Immunol, 2015, vol. 194. pp. 2110-2116.
Grützke B, Hucke S, Gross CC, et al. Fingolimod treatment promotes regulatory phenotype and function of B cells [J]. Ann Clin Transl Neurol. 2015, vol. 2. pp. 119-130.
Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease [J]. Annu Rev Immunol, 2010 vol. 28. pp. 573-621.
D’Ambrosio A, Cossu A, Amendola A, et al. Lamina propria CD4+LAP+ regulatory T cells are increased in active ulcerative colitis but show increased IL-17 expression and reduced suppressor activity [J]. J Crohns Colitis, 2016, vol. 10. pp. 346-353.
Chao K, Zhang S, Yao J, et al. Imbalances of CD4(+)T-cell subgroups in Crohn’s disease andtheir relationship with disease activity and prognosis [J]. J Gastroenterol Hepatol, 2014, vol. 29. pp. 1808-1814.
Furfaro F, Gilardi D, Allocca M, et al. IL-23 Blockade for Crohn s disease: next generation of anti-cytokine therapy [J]. Exp Rev ClinImmunol, 2017 vol. 13. pp. 457-467.
Wang R, Hasnain SZ, Tong H, et al. Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model [J]. Inflamm Bowel Dis, 2015, vol. 21. pp. 973-984.
Jiang W, Su J, Zhang X, et al. Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease [J]. Inflamm Res, 2014 vol. 63. pp. 943-950.
Lee SY, Lee SH, Yang EJ, et al. Metformin Ameliorates Inflammatory Bowel Disease by suppression of the STAT3 SignalingPathway and Regulation of the between Th17/Treg Balance [J]. PLoS One. 2015, vol. 10. pp. e0135858.
Zhao XJ, Ma JJ, Zhu YJ, et al. Changes of Th17/Treg cell ratio and serum inflammatory activity index in patients with Crohn's disease and its clinical significance [J]. Journal of Nanjing Medical University (Natural Science), 2017 vol. 37. pp. 1000-1004.
Sudzius G, Mieliauskaite D, Butrimiene I, et al. Activity of T-helper cells in patients with primary Sjogren's syndrome [J]. In Vivo, 2013, vol. 27. pp. 263-268.
Wang XM. Expression of interleukin-17 in labial gland tissue and peripheral blood of patients with primary Sjogren's syn-drome [D]. Anhui Medical University, 2009.
Yu ZB, Zhang FX, Zheng GM, et al. Expression and significance of Th17 cytokines in the labial glands of primary Sjögren's syndrome [J]. Journal of Clinical Medicine, 2013, vol. 28. pp. 1327-1329, 1332
Wang WJ, Wen JT. Detection and significance of Th17cells in peripheral blood of patients with primary Sjogren's syndrome [J]. Chinese Journal of Laboratory Diagnosis, 2011, vol. 15. pp. 1039-1040.
Sumida T, Iizuka M, Asashima H, et al. Pathogenicrole of anti-M3 Muscarinicacetylcholine receptor immune response in Sjo-gre, ns syndrome [J]. Presse Med, 2012, vol. 41. pp. 461-466.
Zhu JD, Wang ZQ, Zhang PN. Observation of immune imbalance between Th17 and regulatory T cells in patients with Sjo-gren's syndrome [J]. Journal of Radioimmunology, 2012, vol. 25. pp. 301-303.
Alunno A, Petrillo MG, Nocentini G, et al. Characterization of a new regulatory CD+4 T cell subset in primary Sjgren' s syn-drome [J]. Rheumatology (Oxford), 2013, vol. 52. pp. 1387-1396.
Gao LX, Zhang FC, Ma YM, et al. Abnormal expression of regulatory T cells in primary Sjogren's syndrome [J]. Chinese Journal of Rheumatology, 2012, vol. 16. pp. 477-480.
Zheng HX, Yu JN, Tao YJ, et al. Expression and significance of CD4+CD25 high regulatory T cells in peripheral blood of patients with primary Sjogren's syndrome [J]. Zhejiang Journal of Practical Medicine, 2010, vol. 15. pp. 3-4.
Li DM, Li XM, Li XP, et al. Detection and significance of CD4+CD25+CD127 low/-T cells in peripheral blood of patients with primary Sjogren's syndrome [J]. Journal of Anhui Medical University, 2009, vol. 44. pp. 482-486.
Glick AB, Wodzinski A, Fu P, et al. Impairment of regulatory T cell function in autoimmune thyroid disease [J]. Thyroid, 2013, vol. 23. pp. 871-878.
Marazuela M, García-López MA, Figueroa-Vega N, et al. Regulatory T cells in human autoimmune thyroid disease [J]. J ClinEndocrinol Metab. 2006, vol. 91. pp. 3639-3646.
Wang Y, Wu LP, Fu J, et al. Hyperthyroid monkeys: a nonhuman primate model of experimental Graves’ disease [J]. J Endocri-nol, 2013, vol. 219. pp. 183-193.
Kahaly GJ, Shimony O, Gellman YN, et al. RegulatoryT-cells in Graves' orbitopathy: baseline findings and immunomodula-tion by anti-Tlymphocyte globulin [J]. J Clin Endo crinol Metab. 2011, vol. 96. pp. 422-429.
Tang DH, Xu EL, Wu L. Quantitative and functional analysis of CD4+and CD25+regulatory T cells in peripheral blood of patients with Graves disease [J]. Journal of Navy Medicine, 2008, vol. 128. pp. 114-118.
Peng D, Xu B, Wang Y, et al. A high frequency of circulating Th22 and Th17 cells in patients with new onset Graves’ disease [J/OA]. PLoS One, 2013, vol. 8. pp. e68446.
Mao C, Wang S, Xiao Y, et al. Impairment of regulatory capacity of CD4+CD25+regulatoryTcells mediated by dendritic cell polarization and hyperthyroidism in Graves’ disease [J]. J Immunol, 2011, vol. 186. pp. 4734-4743.
Klatka M, Grywalska E, Partyka M, et al. Th17 and Treg cells in adolescents with Graves’ disease. Impact of treatment with methimazole on these cell subsets [J]. Autoimmunity, 2014, vol. 47. pp. 201-211.
Chen WZ. Study on Th17/Treg immune imbalance in patients with Hashimoto's thyroiditis [D]. Master's thesis of Nanchang University, 2012.
Zhao JY. Detection and significance of Th17 cells in patients with Hashimoto's thyroiditis and Graves disease [D]. Master's thesis of Jilin University, 2012.
de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1 [J]. Gastroenterology, 2014, vol. 147. pp. 443-452, e5.
Zhao L, Tang Y, You Z, et al. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepa-tic interleukin-6 expression [J]. PLoS One, 2011, vol. 6. pp. e18909.
Ferri S, Longhi MS, De Molo C, et al. A multifaceted imbalance of T cells with regulatory function characterizes type 1 auto-immune hepatitis [J]. Hepatology, 2010, vol. 52. pp. 999-1007.
Holder BS, Grant CR, Liberal R, et al. Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2 [J]. J Autoimmun. 2014, vol. 53. pp. 26-32.
Peiseler M, Sebode M, Franke B, et al. FOXP3+regulatory T cells in autoimmune hepatitis are fully functional and not reduc-ed in frequency [J]. J Hepatol. 2012, vol. 57. pp. 125-132.
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