KEGG   PATHWAY: oaa04659
Entry
oaa04659                    Pathway                                
Name
Th17 cell differentiation - Ornithorhynchus anatinus (platypus)
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 system
Pathway map
oaa04659  Th17 cell differentiation
oaa04659

Other DBs
GO: 0072539
Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
100073424  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100073470  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
100073530  IL6ST; interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
100073613  IKBKG; NF-kappa-B essential modulator [KO:K07210]
100073776  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
100074305  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
100074625  [KO:K08524]
100074633  RELA; transcription factor p65 isoform X1 [KO:K04735]
100075021  FOS; proto-oncogene c-Fos [KO:K04379]
100075823  FOXP3; forkhead box protein P3 isoform X1 [KO:K10163]
100076033  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
100076965  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
100077136  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100077893  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
100078190  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
100078396  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446]
100078507  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
100078574  IFNGR1; interferon gamma receptor 1 [KO:K05132]
100078757  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100078889  IL17A; interleukin-17A [KO:K05489]
100078925  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100078988  [KO:K05494]
100079322  ORAN-DRA; MHC class II DR alpha precursor [KO:K06752]
100079376  IL21R; LOW QUALITY PROTEIN: interleukin-21 receptor [KO:K05075]
100079451  IRF4; interferon regulatory factor 4 [KO:K09445]
100079751  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100079841  RORA; nuclear receptor ROR-alpha isoform X1 [KO:K08532]
100079998  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
100080039  HIF1A; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
100080327  IL22; interleukin-22 [KO:K05445]
100081686  [KO:K04723]
100081726  IL23R; interleukin-23 receptor isoform X1 [KO:K05065]
100082351  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
100082553  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
100082590  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100082718  CD247; T-cell surface glycoprotein CD3 zeta chain isoform X1 [KO:K06453]
100082891  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
100082981  JAK1; tyrosine-protein kinase JAK1 isoform X1 [KO:K11217] [EC:2.7.10.2]
100083243  [KO:K09093]
100083298  IL6; interleukin-6 [KO:K05405]
100083438  IFNGR2; interferon gamma receptor 2 isoform X1 [KO:K05133]
100083665  PPP3R1; calcineurin subunit B type 1 isoform X1 [KO:K06268]
100083673  NFKBIE; NF-kappa-B inhibitor epsilon [KO:K05872]
100083819  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100083890  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
100084073  IL1R1; interleukin-1 receptor type 1 [KO:K04386]
100084126  AHR; aryl hydrocarbon receptor [KO:K09093]
100084162  TBX21; T-box transcription factor TBX21 [KO:K10166]
100085002  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
100085025  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
100085480  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100085612  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
100085963  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
100086487  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100087266  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
100087467  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
100087533  IL23A; interleukin-23 subunit alpha [KO:K05426]
100087932  STAT3; signal transducer and activator of transcription 3 isoform X2 [KO:K04692]
100088053  [KO:K06752]
100088072  [KO:K06752]
100089224  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
100089518  RORC; nuclear receptor ROR-gamma [KO:K08534]
100090081  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100090795  CD3G; T-cell surface glycoprotein CD3 gamma chain [KO:K06452]
100090811  [KO:K06450]
100091159  EBI3; interleukin-27 subunit beta [KO:K24476]
100091330  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
100092264  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100092358  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
100092826  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
100092851  IL2RB; interleukin-2 receptor subunit beta [KO:K05069]
100092915  STAT5B; LOW QUALITY PROTEIN: signal transducer and activator of transcription 5B [KO:K11224]
100093026  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100680688  IL27; interleukin-27 subunit alpha [KO:K22629]
100681576  TYK2; LOW QUALITY PROTEIN: non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
103164647  CD3E; T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
103164911  IL4R; interleukin-4 receptor subunit alpha [KO:K05071]
103165286  [KO:K04519]
103165339  CD4; T-cell surface glycoprotein CD4 isoform X1 [KO:K06454]
103165385  IL2RA; interleukin-2 receptor subunit alpha isoform X2 [KO:K05068]
103165717  IL27RA; interleukin-27 receptor subunit alpha [KO:K19598]
103166389  [KO:K06752]
103171440  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
114806029  [KO:K09445]
114807636  [KO:K06752]
114807666  [KO:K06752]
114808214  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
114808669  [KO:K09445]
114809080  LAT; linker for activation of T-cells family member 1 [KO:K07362]
114811257  [KO:K08524]
114812005  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
114812052  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
114812802  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
114817203  RXRG; retinoic acid receptor RXR-gamma [KO:K08526]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00777  Retinoate
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:23325835
  Authors
Muranski P, Restifo NP
  Title
Essentials of Th17 cell commitment and plasticity.
  Journal
Blood 121:2402-14 (2013)
DOI:10.1182/blood-2012-09-378653
Reference
PMID:19379825
  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
Microbes Infect 11:599-611 (2009)
DOI:10.1016/j.micinf.2009.04.007
Reference
PMID:21084214
  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
Cytokine Growth Factor Rev 21:425-34 (2010)
DOI:10.1016/j.cytogfr.2010.10.006
Reference
PMID:18166487
  Authors
Chen Z, Laurence A, O'Shea JJ
  Title
Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation.
  Journal
Semin Immunol 19:400-8 (2007)
DOI:10.1016/j.smim.2007.10.015
Reference
PMID:22640807
  Authors
Maddur MS, Miossec P, Kaveri SV, Bayry J
  Title
Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies.
  Journal
Am J Pathol 181:8-18 (2012)
DOI:10.1016/j.ajpath.2012.03.044
Reference
PMID:23036716
  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
Immunol Lett 148:97-109 (2012)
DOI:10.1016/j.imlet.2012.09.007
Reference
PMID:18408735
  Authors
Dong C
  Title
TH17 cells in development: an updated view of their molecular identity and genetic programming.
  Journal
Nat Rev Immunol 8:337-48 (2008)
DOI:10.1038/nri2295
Reference
PMID:20054607
  Authors
Torchinsky MB, Blander JM
  Title
T helper 17 cells: discovery, function, and physiological trigger.
  Journal
Cell Mol Life Sci 67:1407-21 (2010)
DOI:10.1007/s00018-009-0248-3
Reference
PMID:19381306
  Authors
Jetten AM
  Title
Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.
  Journal
Nucl Recept Signal 7:e003 (2009)
DOI:10.1621/nrs.07003
Reference
PMID:22133865
  Authors
Oestreich KJ, Weinmann AS
  Title
T-bet employs diverse regulatory mechanisms to repress transcription.
  Journal
Trends Immunol 33:78-83 (2012)
DOI:10.1016/j.it.2011.10.005
Reference
PMID:24325586
  Authors
Manni ML, Robinson KM, Alcorn JF
  Title
A tale of two cytokines: IL-17 and IL-22 in asthma and infection.
  Journal
Expert Rev Respir Med 8:25-42 (2014)
DOI:10.1586/17476348.2014.854167
Reference
PMID:21776333
  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
Self Nonself 2:35-42 (2011)
DOI:10.4161/self.2.1.15639
Reference
PMID:20488727
  Authors
Nakayama T, Yamashita M
  Title
The TCR-mediated signaling pathways that control the direction of helper T cell differentiation.
  Journal
Semin Immunol 22:303-9 (2010)
DOI:10.1016/j.smim.2010.04.010
Reference
PMID:21151104
  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
Nat Immunol 12:96-104 (2011)
DOI:10.1038/ni.1969
Reference
PMID:22754770
  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
Oncoimmunology 1:510-515 (2012)
DOI:10.4161/onci.19457
Reference
PMID:18362914
  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
Nature 453:106-9 (2008)
DOI:10.1038/nature06881
Reference
PMID:17768419
  Authors
Deenick EK, Tangye SG
  Title
Autoimmunity: IL-21: a new player in Th17-cell differentiation.
  Journal
Immunol Cell Biol 85:503-5 (2007)
DOI:10.1038/sj.icb.7100114
Reference
PMID:26253381
  Authors
Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD
  Title
IL-27-induced modulation of autoimmunity and its therapeutic potential.
  Journal
Autoimmun Rev 14:1131-41 (2015)
DOI:10.1016/j.autrev.2015.08.001
Reference
PMID:16200068
  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
Nat Immunol 6:1133-41 (2005)
DOI:10.1038/ni1261
Reference
PMID:22324470
  Authors
Zhu S, Qian Y
  Title
IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential.
  Journal
Clin Sci (Lond) 122:487-511 (2012)
DOI:10.1042/CS20110496
Related
pathway
oaa04010  MAPK signaling pathway
oaa04020  Calcium signaling pathway
oaa04064  NF-kappa B signaling pathway
oaa04066  HIF-1 signaling pathway
oaa04350  TGF-beta signaling pathway
oaa04514  Cell adhesion molecules
oaa04620  Toll-like receptor signaling pathway
oaa04630  JAK-STAT signaling pathway
oaa04660  T cell receptor signaling pathway
oaa05321  Inflammatory bowel disease
oaa05323  Rheumatoid arthritis
KO pathway
ko04659   

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