KEGG   PATHWAY: oas04659
Entry
oas04659                    Pathway                                
Name
Th17 cell differentiation - Ovis aries (sheep)
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
oas04659  Th17 cell differentiation
oas04659

Other DBs
GO: 0072539
Organism
Ovis aries (sheep) [GN:oas]
Gene
443539  IL1B; interleukin-1 beta precursor [KO:K04519]
101103054  IL1R1; interleukin-1 receptor type 1 isoform X1 [KO:K04386]
101108354  IL1RAP; interleukin-1 receptor accessory protein isoform X3 [KO:K04723]
100194428  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100217411  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
101116223  MAPK11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
101115956  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100271659  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101111234  IRF4; interferon regulatory factor 4 isoform X1 [KO:K09445]
106991529  interferon regulatory factor 4-like isoform X3 [KO:K09445]
443417  TGFB1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
554326  TGFBR1; TGF-beta receptor type-1 isoform X2 [KO:K04674] [EC:2.7.11.30]
494191  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
101114231  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
443169  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
443171  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100862657  IL21; interleukin-21 precursor [KO:K05434]
100820753  IL21R; interleukin-21 receptor precursor [KO:K05075]
101103538  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
101110716  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
101112816  JAK3; tyrosine-protein kinase JAK3 isoform X2 [KO:K11218] [EC:2.7.10.2]
443406  IL6; interleukin-6 precursor [KO:K05405]
101103369  IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
101113174  IL6ST; interleukin-6 receptor subunit beta [KO:K05060]
101113909  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
100462692  IL23A; interleukin-23 subunit alpha precursor [KO:K05426]
101103528  IL23R; interleukin-23 receptor [KO:K05065]
101110054  IL12RB1; interleukin-12 receptor subunit beta-1 precursor [KO:K05063]
101117248  TYK2; non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
100294659  STAT3; signal transducer and activator of transcription 3 isoform X10 [KO:K04692]
101119104  RORC; nuclear receptor ROR-gamma isoform X4 [KO:K08534]
101102986  RORA; nuclear receptor ROR-alpha isoform X3 [KO:K08532]
443519  HIF1A; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
100127209  HSP90AA1; heat shock protein HSP 90-alpha isoform X2 [KO:K04079]
101117797  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
443467  AHR; aryl hydrocarbon receptor isoform X1 [KO:K09093]
101103931  IL17A; interleukin-17A [KO:K05489]
101104186  IL17F; interleukin-17F [KO:K05494]
100885770  IL22; interleukin-22 precursor [KO:K05445]
100144749  DYA; MHC class II antigen DY alpha precursor [KO:K06752]
101108696  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
101108962  DQA; HLA class II histocompatibility antigen, DQ alpha 2 chain precursor [KO:K06752]
101119342  OVAR-DRB1; DLA class II histocompatibility antigen, DR-1 beta chain-like precursor [KO:K06752]
101109747  mamu class II histocompatibility antigen, DR alpha chain-like precursor [KO:K06752]
101108961  DLA class II histocompatibility antigen, DR-1 beta chain-like isoform X2 [KO:K06752]
101109219  HLA class II histocompatibility antigen, DO beta chain isoform X1 [KO:K06752]
101109746  HLA class II histocompatibility antigen, DM beta chain isoform X2 [KO:K06752]
101110545  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
101116099  HLA class II histocompatibility antigen, DM alpha chain isoform X2 [KO:K06752]
101114758  LOW QUALITY PROTEIN: DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
101118514  boLa class II histocompatibility antigen, DQB*0101 beta chain isoform X2 [KO:K06752]
101120392  boLa class II histocompatibility antigen, DQB*0101 beta chain isoform X2 [KO:K06752]
101115073  rano class II histocompatibility antigen, A beta chain isoform X1 [KO:K06752]
443509  CD4; T-cell surface glycoprotein CD4 precursor [KO:K06454]
100216439  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
443437  CD3E; T-cell surface glycoprotein CD3 epsilon chain precursor [KO:K06451]
443398  T-cell surface glycoprotein CD3 gamma chain isoform X2 [KO:K06452]
101114438  T cell receptor beta variable 7-9 [KO:K10785]
443436  CD247; T-cell surface glycoprotein CD3 zeta chain precursor [KO:K06453]
443397  CD3D; T-cell surface glycoprotein CD3 delta chain precursor [KO:K06450]
101112639  tyrosine-protein kinase ZAP-70 isoform X1 [KO:K07360] [EC:2.7.10.2]
101110725  LAT; linker for activation of T-cells family member 1 isoform X3 [KO:K07362]
101103341  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
101108104  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X2 [KO:K04348] [EC:3.1.3.16]
101115429  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X4 [KO:K04348] [EC:3.1.3.16]
101122602  PPP3CA; protein phosphatase 3 catalytic subunit alpha isoform X1 [KO:K04348] [EC:3.1.3.16]
101120802  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
114108765  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
101108097  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X6 [KO:K04446]
101119239  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
101117607  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X3 [KO:K17333]
101113426  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
101111143  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
780484  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
101107332  IKBKG; NF-kappa-B essential modulator isoform X3 [KO:K07210]
780520  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
101113618  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
101118312  NFKBIE; NF-kappa-B inhibitor epsilon isoform X1 [KO:K05872]
101108228  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X2 [KO:K02580]
101102191  RELA; transcription factor p65 [KO:K04735]
101115485  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
101123008  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
443218  FOS; protein c-Fos [KO:K04379]
101116201  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120826  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120665  MAPK10; mitogen-activated protein kinase 10 isoform X2 [KO:K04440] [EC:2.7.11.24]
443219  JUN; transcription factor Jun [KO:K04448]
101122781  IL4; interleukin-4 precursor [KO:K05430]
101109063  IL4R; interleukin-4 receptor subunit alpha isoform X1 [KO:K05071]
101102134  STAT6; signal transducer and activator of transcription 6 isoform X1 [KO:K11225]
780483  GATA3; trans-acting T-cell-specific transcription factor GATA-3 [KO:K17895]
101108280  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
101122495  IL27; interleukin-27 subunit alpha [KO:K22629]
101113064  EBI3; interleukin-27 subunit beta [KO:K24476]
101102232  IL27RA; interleukin-27 receptor subunit alpha isoform X1 [KO:K19598]
443396  IFNG; interferon gamma precursor [KO:K04687]
101112907  IFNGR1; interferon gamma receptor 1 isoform X2 [KO:K05132]
101122484  IFNGR2; interferon gamma receptor 2 isoform X2 [KO:K05133]
100307049  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
101118711  TBX21; T-box transcription factor TBX21 [KO:K10166]
443401  IL2; interleukin-2 precursor [KO:K05429]
443435  IL2RA; interleukin-2 receptor subunit alpha precursor [KO:K05068]
101107088  IL2RB; interleukin-2 receptor subunit beta isoform X2 [KO:K05069]
443419  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
101122961  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
100240742  FOXP3; forkhead box protein P3 [KO:K10163]
101107973  RARA; retinoic acid receptor alpha isoform X2 [KO:K08527]
114113852  RXRA; retinoic acid receptor RXR-alpha isoform X2 [KO:K08524]
101110798  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
101111845  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
oas04010  MAPK signaling pathway
oas04020  Calcium signaling pathway
oas04064  NF-kappa B signaling pathway
oas04066  HIF-1 signaling pathway
oas04350  TGF-beta signaling pathway
oas04514  Cell adhesion molecules
oas04620  Toll-like receptor signaling pathway
oas04630  JAK-STAT signaling pathway
oas04660  T cell receptor signaling pathway
oas05321  Inflammatory bowel disease
oas05323  Rheumatoid arthritis
KO pathway
ko04659   
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