KEGG   PATHWAY: gvr04659
Entry
gvr04659                    Pathway                                
Name
Th17 cell differentiation - Galeopterus variegatus (Sunda flying lemur)
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
gvr04659  Th17 cell differentiation
gvr04659

Other DBs
GO: 0072539
Organism
Galeopterus variegatus (Sunda flying lemur) [GN:gvr]
Gene
103595825  IL1B; interleukin-1 beta [KO:K04519]
103610948  IL1R1; interleukin-1 receptor type 1 [KO:K04386]
103599674  IL1RAP; interleukin-1 receptor accessory protein isoform X1 [KO:K04723]
103607428  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
103607442  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
103587477  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
103587478  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
103601062  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
103594192  interferon regulatory factor 4-like [KO:K09445]
103598792  IRF4; interferon regulatory factor 4 [KO:K09445]
103599185  transforming growth factor beta-1 [KO:K13375]
103599191  transforming growth factor beta-1-like [KO:K13375]
103587310  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
103591905  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
103595293  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
103590291  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
103600109  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
103605901  IL21; interleukin-21 [KO:K05434]
103585611  IL21R; interleukin-21 receptor [KO:K05075]
103586318  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
103591505  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
103593677  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
103585928  IL6; interleukin-6 [KO:K05405]
103608410  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
103588371  IL6ST; interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
103594579  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
103594015  IL23A; interleukin-23 subunit alpha [KO:K05426]
103600737  IL23R; interleukin-23 receptor [KO:K05065]
103593685  IL12RB1; LOW QUALITY PROTEIN: interleukin-12 receptor subunit beta-1 [KO:K05063]
103594750  TYK2; non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
103595356  signal transducer and activator of transcription 3-like [KO:K04692]
103592423  RORC; nuclear receptor ROR-gamma isoform X1 [KO:K08534]
103596674  RORA; nuclear receptor ROR-alpha [KO:K08532]
103585213  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
103588342  LOW QUALITY PROTEIN: heat shock protein HSP 90-beta-like [KO:K04079]
103595468  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
103590414  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
103591489  aryl hydrocarbon receptor-like [KO:K09093]
103606115  AHR; aryl hydrocarbon receptor [KO:K09093]
103605142  IL17A; interleukin-17A [KO:K05489]
103605143  IL17F; interleukin-17F [KO:K05494]
103604289  IL22; interleukin-22 [KO:K05445]
103608747  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
103602253  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
103602254  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
103602258  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
103602259  HLA class II histocompatibility antigen, DP alpha 1 chain-like isoform X1 [KO:K06752]
103602260  HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
103610538  mamu class II histocompatibility antigen, DR alpha chain [KO:K06752]
103581584  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
103582505  HLA class II histocompatibility antigen, DRB1-9 beta chain-like [KO:K06752]
103582509  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
103582925  HLA class II histocompatibility antigen, DRB1-4 beta chain-like [KO:K06752]
103583986  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
103584069  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
103597932  HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
103597933  HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
103586411  CD4; T-cell surface glycoprotein CD4 [KO:K06454]
103594929  LCK; tyrosine-protein kinase Lck isoform X1 [KO:K05856] [EC:2.7.10.2]
103592268  CD3E; T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
103592270  CD3G; T-cell surface glycoprotein CD3 gamma chain [KO:K06452]
103582933  uncharacterized protein LOC103582933 [KO:K10784]
103604227  uncharacterized protein LOC103604227 [KO:K10784]
103605353  uncharacterized protein LOC103605353 [KO:K10785]
103601908  CD247; T-cell surface glycoprotein CD3 zeta chain [KO:K06453]
103592269  CD3D; T-cell surface glycoprotein CD3 delta chain isoform X1 [KO:K06450]
103610308  LOW QUALITY PROTEIN: tyrosine-protein kinase ZAP-70-like [KO:K07360] [EC:2.7.10.2]
103582470  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
103595586  LAT; linker for activation of T-cells family member 1 isoform X1 [KO:K07362]
103606318  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
103591114  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16]
103598106  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
103598210  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
103604521  PPP3R2; calcineurin subunit B type 2 isoform X1 [KO:K06268]
103585050  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
103598251  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
103586032  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333]
103594130  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
103588798  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
103589266  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
103604367  IKBKG; NF-kappa-B essential modulator [KO:K07210]
103591436  NFKBIA; LOW QUALITY PROTEIN: NF-kappa-B inhibitor alpha [KO:K04734]
103591464  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
103590415  NFKBIE; NF-kappa-B inhibitor epsilon [KO:K05872]
103597025  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
103595334  RELA; transcription factor p65 [KO:K04735]
103592192  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103600324  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103605891  FOS; proto-oncogene c-Fos [KO:K04379]
103582610  mitogen-activated protein kinase 9-like isoform X1 [KO:K04440] [EC:2.7.11.24]
103603521  mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
103585627  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
103606635  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
103592390  JUN; transcription factor AP-1 [KO:K04448]
103589624  IL4; interleukin-4 [KO:K05430]
103585606  IL4R; interleukin-4 receptor subunit alpha [KO:K05071]
103596102  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
103589374  GATA3; trans-acting T-cell-specific transcription factor GATA-3 [KO:K17895]
103586963  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
103595600  IL27; interleukin-27 subunit alpha [KO:K22629]
103600173  EBI3; interleukin-27 subunit beta [KO:K24476]
103585133  IL27RA; interleukin-27 receptor subunit alpha isoform X1 [KO:K19598]
103609732  interferon gamma-like [KO:K04687]
103605815  interferon gamma-like [KO:K04687]
103591435  IFNGR1; interferon gamma receptor 1 [KO:K05132]
103585995  IFNGR2; interferon gamma receptor 2 [KO:K05133]
103588074  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
103589105  TBX21; T-box transcription factor TBX21 [KO:K10166]
103593609  IL2; interleukin-2 [KO:K05429]
103607987  interleukin-2 receptor subunit alpha-like [KO:K05068]
103606392  IL2RB; interleukin-2 receptor subunit beta [KO:K05069]
103595355  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
103595352  LOW QUALITY PROTEIN: signal transducer and activator of transcription 5B-like [KO:K11224]
103602698  FOXP3; forkhead box protein P3 isoform X1 [KO:K10163]
103607734  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
103591675  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
103597936  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
103607349  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
gvr04010  MAPK signaling pathway
gvr04020  Calcium signaling pathway
gvr04064  NF-kappa B signaling pathway
gvr04066  HIF-1 signaling pathway
gvr04350  TGF-beta signaling pathway
gvr04514  Cell adhesion molecules
gvr04620  Toll-like receptor signaling pathway
gvr04630  JAK-STAT signaling pathway
gvr04660  T cell receptor signaling pathway
gvr05321  Inflammatory bowel disease
gvr05323  Rheumatoid arthritis
KO pathway
ko04659   
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