Entry Name Th17 cell differentiation
Description Interleukin (IL)-17-producing helper T (Th17) cells serve as a subset of CD4+ T cells involved in epithelial cell- and neutrophil mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases. In vivo, Th17 differentiation requires antigen presentation and co-stimulation, and activation of antigen presenting-cells (APCs) to produce TGF-beta, IL-6, IL-1, IL-23 and IL-21. This initial activation results in the activation and up-regulation of STAT3, ROR(gamma)t and other transcriptional factors in CD4+ T cells, which bind to the promoter regions of the IL-17, IL-21 and IL-22 genes and induce IL-17, IL-21 and IL-22. In contrast, the differentiation of Th17 cells and their IL-17 expression are negatively regulated by IL-2, Th2 cytokine IL-4, IL-27 and Th1 cytokine IFN-gamma through STAT5, STAT6 and STAT1 activation, respectively. Retinoid acid and the combination of IL-2 and TGF-beta upregulate Foxp3, which also downregulates cytokines like IL-17 and IL-21. The inhibition of Th17 differentiation may serve as a protective strategy to 'fine-tune' the expression IL-17 so it does not cause excessive inflammation. Thus, balanced differentiation of Th cells is crucial for immunity and host protection.
Class Organismal Systems; Immune systemBRITE hierarchy
Pathway map Other DBs Orthology K01116 PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11 ]
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02581 NFKBIB; NF-kappa-B inhibitor beta
K04079 HSP90A, htpG; molecular chaperone HtpG
K04348 PPP3C, CNA; serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16 ]
K04379 FOS; proto-oncogene protein c-fos
K04386 IL1R1, CD121a; interleukin 1 receptor type I
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04446 NFATC1, NFAT2, NFATC; nuclear factor of activated T-cells, cytoplasmic 1
K04448 JUN; transcription factor AP-1
K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K04500 SMAD2; mothers against decapentaplegic homolog 2
K04501 SMAD4; mothers against decapentaplegic homolog 4
K04519 IL1B; interleukin 1 beta
K04692 STAT3; signal transducer and activator of transcription 3
K04723 IL1RAP; interleukin 1 receptor accessory protein
K04734 NFKBIA; NF-kappa-B inhibitor alpha
K04735 RELA; transcription factor p65
K05055 IL6R, CD126; interleukin 6 receptor
K05060 IL6ST, GP130, CD130; interleukin 6 signal transducer
K05063 IL12RB1, CD212; interleukin 12 receptor beta-1
K05065 IL23R; interleukin 23 receptor
K05068 IL2RA, CD25; interleukin 2 receptor alpha
K05069 IL2RB, CD122; interleukin 2 receptor beta
K05070 IL2RG, CD132; interleukin 2 receptor gamma
K05071 IL4R, CD124; interleukin 4 receptor
K05075 IL21R, CD360; interleukin 21 receptor
K05132 IFNGR1, CD119; interferon gamma receptor 1
K05133 IFNGR2; interferon gamma receptor 2
K05426 IL23A; interleukin 23 subunit alpha
K05445 IL22, IL-TIF; interleukin 22
K05489 IL17A, CTLA8; interleukin 17A
K05494 IL17F, ML1; interleukin 17F
K05856 LCK; lymphocyte cell-specific protein tyrosine kinase [EC:2.7.10.2 ]
K05872 NFKBIE; NF-kappa-B inhibitor epsilon
K06268 PPP3R, CNB; serine/threonine-protein phosphatase 2B regulatory subunit
K06450 CD3D; T-cell surface glycoprotein CD3 delta chain
K06451 CD3E; T-cell surface glycoprotein CD3 epsilon chain
K06452 CD3G; T-cell surface glycoprotein CD3 gamma chain
K06453 CD3Z, CD247; CD3Z antigen, zeta polypeptide
K06454 CD4; T-cell surface glycoprotein CD4
K06752 MHC2; MHC class II antigen
K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1 ]
K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07210 IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma
K07362 LAT; linker for activation of T cells family member 1
K08268 HIF1A; hypoxia-inducible factor 1 alpha
K08367 RUNX1, AML1; runt-related transcription factor 1
K08524 RXRA, NR2B1; retinoid X receptor alpha
K08525 RXRB, NR2B2; retinoid X receptor beta
K08526 RXRG, NR2B3; retinoid X receptor gamma
K08527 RARA, NR1B1; retinoic acid receptor alpha
K08532 NR1F1, RORA; RAR-related orphan receptor alpha
K08534 NR1F3, RORC; RAR-related orphan receptor gamma
K09093 AHR; aryl hydrocarbon receptor
K09445 IRF4; interferon regulatory factor 4
K10163 FOXP3, IPEX; forkhead box P3
K10166 TBX21; T-box protein 21
K10784 TRAV; T cell receptor alpha chain V region
K10785 TRBV; T-cell receptor beta chain V region
K11220 STAT1; signal transducer and activator of transcription 1
K11223 STAT5A; signal transducer and activator of transcription 5A
K11224 STAT5B; signal transducer and activator of transcription 5B
K11225 STAT6; signal transducer and activator of transcription 6
K13375 TGFB1; transforming growth factor beta-1
K17332 NFATC2, NFAT1, NFATP; nuclear factor of activated T-cells, cytoplasmic 2
K17333 NFATC3, NFAT4; nuclear factor of activated T-cells, cytoplasmic 3
K17895 GATA3; GATA-binding protein 3
K19598 IL27RA; interleukin 27 receptor alpha
K22629 IL27, IL27A; interleukin 27 subunit alpha
K23605 SMAD3; mothers against decapentaplegic homolog 3
K24476 EBI3, IL27B; interleukin 27 subunit beta
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
Reference Authors Muranski P, Restifo NP
Title Essentials of Th17 cell commitment and plasticity.
Journal Reference Authors O'Shea JJ, Steward-Tharp SM, Laurence A, Watford WT, Wei L, Adamson AS, Fan S
Title Signal transduction and Th17 cell differentiation.
Journal Reference Authors Hirahara K, Ghoreschi K, Laurence A, Yang XP, Kanno Y, O'Shea JJ
Title Signal transduction pathways and transcriptional regulation in Th17 cell differentiation.
Journal Reference Authors Chen Z, Laurence A, O'Shea JJ
Title Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation.
Journal Reference Authors Maddur MS, Miossec P, Kaveri SV, Bayry J
Title Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies.
Journal Reference Authors Hemdan NY, Birkenmeier G, Wichmann G
Title Key molecules in the differentiation and commitment program of T helper 17 (Th17) cells up-to-date.
Journal Reference Authors Dong C
Title TH17 cells in development: an updated view of their molecular identity and genetic programming.
Journal Reference Authors Torchinsky MB, Blander JM
Title T helper 17 cells: discovery, function, and physiological trigger.
Journal Reference Authors Jetten AM
Title Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.
Journal Reference Authors Oestreich KJ, Weinmann AS
Title T-bet employs diverse regulatory mechanisms to repress transcription.
Journal Reference Authors Manni ML, Robinson KM, Alcorn JF
Title A tale of two cytokines: IL-17 and IL-22 in asthma and infection.
Journal Reference Authors Sha Y, Markovic-Plese S
Title A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases.
Journal Reference Authors Nakayama T, Yamashita M
Title The TCR-mediated signaling pathways that control the direction of helper T cell differentiation.
Journal Reference Authors Lazarevic V, Chen X, Shim JH, Hwang ES, Jang E, Bolm AN, Oukka M, Kuchroo VK, Glimcher LH
Title T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORgammat.
Journal Reference Authors Pan F, Barbi J, Pardoll DM
Title Hypoxia-inducible factor 1: A link between metabolism and T cell differentiation and a potential therapeutic target.
Journal Reference Authors Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B
Title The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.
Journal Reference Authors Deenick EK, Tangye SG
Title Autoimmunity: IL-21: a new player in Th17-cell differentiation.
Journal Reference Authors Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD
Title IL-27-induced modulation of autoimmunity and its therapeutic potential.
Journal Reference Authors Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C
Title A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
Journal Reference Authors Zhu S, Qian Y
Title IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential.
Journal Related ko04064 NF-kappa B signaling pathway
ko04620 Toll-like receptor signaling pathway
ko04660 T cell receptor signaling pathway
