KEGG   PATHWAY: oga04659
Entry
oga04659                    Pathway                                
Name
Th17 cell differentiation - Otolemur garnettii (small-eared galago)
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
oga04659  Th17 cell differentiation
oga04659

Other DBs
GO: 0072539
Organism
Otolemur garnettii (small-eared galago) [GN:oga]
Gene
100944877  IL1B; interleukin-1 beta [KO:K04519]
100959140  IL1R1; interleukin-1 receptor type 1 [KO:K04386]
100952305  IL1RAP; interleukin-1 receptor accessory protein isoform X1 [KO:K04723]
100956269  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100957118  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100963993  MAPK11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
100964304  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100957753  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
105886818  LOW QUALITY PROTEIN: interferon regulatory factor 4-like [KO:K09445]
100951716  IRF4; interferon regulatory factor 4 isoform X2 [KO:K09445]
100949640  TGFB1; transforming growth factor beta-1 isoform X2 [KO:K13375]
100953115  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100960821  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
100960336  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
100962223  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
100955502  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100953479  IL21; interleukin-21 [KO:K05434]
100956406  IL21R; interleukin-21 receptor [KO:K05075]
100961176  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
100955095  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
100954742  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
100949231  IL6; LOW QUALITY PROTEIN: interleukin-6 [KO:K05405]
100947685  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
100958958  IL6ST; interleukin-6 receptor subunit beta [KO:K05060]
100948875  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
100943872  IL23A; interleukin-23 subunit alpha [KO:K05426]
100965684  IL23R; interleukin-23 receptor [KO:K05065]
100962079  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
100962299  TYK2; non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
100958469  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
100965452  RORC; nuclear receptor ROR-gamma isoform X2 [KO:K08534]
100940576  RORA; nuclear receptor ROR-alpha [KO:K08532]
100941157  HIF1A; hypoxia-inducible factor 1-alpha isoform X2 [KO:K08268]
100954869  LOW QUALITY PROTEIN: heat shock protein HSP 90-alpha-like [KO:K04079]
100959852  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
100957513  AHR; aryl hydrocarbon receptor [KO:K09093]
100954700  IL17A; interleukin-17A [KO:K05489]
100948092  IL17F; interleukin-17F [KO:K05494]
100944653  IL22; interleukin-22 [KO:K05445]
100960158  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
100961105  HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
105886937  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
100940711  HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
100957117  HLA class II histocompatibility antigen, DRB1-1 beta chain isoform X1 [KO:K06752]
100957422  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
100957736  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
100959019  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
100959331  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
100966668  HLA class II histocompatibility antigen, DQ beta 1 chain-like isoform X1 [KO:K06752]
100956803  HLA class II histocompatibility antigen, DRB1-4 beta chain-like [KO:K06752]
100953378  CD4; T-cell surface glycoprotein CD4 [KO:K06454]
100964949  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
100966596  CD3E; T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
100953225  CD247; T-cell surface glycoprotein CD3 zeta chain [KO:K06453]
100966280  CD3D; T-cell surface glycoprotein CD3 delta chain [KO:K06450]
100944134  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
100957036  LAT; linker for activation of T-cells family member 1 [KO:K07362]
100948398  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
100961754  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
100961025  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16]
100945846  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X2 [KO:K04348] [EC:3.1.3.16]
105886540  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
105887331  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
100940498  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446]
100955220  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X2 [KO:K17332]
100966615  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333]
100963918  PRKCQ; protein kinase C theta type isoform X2 [KO:K18052] [EC:2.7.11.13]
100949554  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
100946157  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100958883  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
100947991  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100942572  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
100961213  NFKBIE; LOW QUALITY PROTEIN: NF-kappa-B inhibitor epsilon [KO:K05872]
100951061  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100957990  RELA; transcription factor p65 isoform X3 [KO:K04735]
100951533  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100957343  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100953435  FOS; proto-oncogene c-Fos [KO:K04379]
100957169  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100967053  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100960275  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100965098  JUN; transcription factor AP-1 [KO:K04448]
100946038  IL4; interleukin-4 isoform X1 [KO:K05430]
100949360  IL4R; interleukin-4 receptor subunit alpha [KO:K05071]
100949888  STAT6; signal transducer and activator of transcription 6 isoform X1 [KO:K11225]
100961930  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
100940749  RUNX1; runt-related transcription factor 1 [KO:K08367]
100958612  IL27; interleukin-27 subunit alpha [KO:K22629]
100952403  EBI3; interleukin-27 subunit beta [KO:K24476]
100950238  IL27RA; interleukin-27 receptor subunit alpha [KO:K19598]
100945607  IFNG; interferon gamma [KO:K04687]
100960904  IFNGR1; interferon gamma receptor 1 isoform X1 [KO:K05132]
100957974  IFNGR2; interferon gamma receptor 2 isoform X1 [KO:K05133]
100956762  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100964222  TBX21; T-box transcription factor TBX21 [KO:K10166]
100942002  IL2; interleukin-2 [KO:K05429]
100967179  IL2RA; interleukin-2 receptor subunit alpha [KO:K05068]
100957798  IL2RB; interleukin-2 receptor subunit beta [KO:K05069]
100958999  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
100955743  signal transducer and activator of transcription 5B [KO:K11224]
100963348  FOXP3; forkhead box protein P3 isoform X2 [KO:K10163]
100948279  RARA; retinoic acid receptor alpha isoform X2 [KO:K08527]
100962073  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
100962161  RXRB; retinoic acid receptor RXR-beta isoform X2 [KO:K08525]
100941535  RXRG; retinoic acid receptor RXR-gamma isoform X1 [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
oga04010  MAPK signaling pathway
oga04020  Calcium signaling pathway
oga04064  NF-kappa B signaling pathway
oga04066  HIF-1 signaling pathway
oga04350  TGF-beta signaling pathway
oga04514  Cell adhesion molecules
oga04620  Toll-like receptor signaling pathway
oga04630  JAK-STAT signaling pathway
oga04660  T cell receptor signaling pathway
oga05321  Inflammatory bowel disease
oga05323  Rheumatoid arthritis
KO pathway
ko04659   
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