KEGG   PATHWAY: ko04659
Entry
ko04659                     Pathway                                
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 system
Pathway map
ko04659  Th17 cell differentiation
ko04659

Other DBs
GO: 0072539
Orthology
K04519  interleukin 1 beta
K04386  interleukin 1 receptor type I
K04723  interleukin 1 receptor accessory protein
K04441  p38 MAP kinase [EC:2.7.11.24]
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K09445  interferon regulatory factor 4
K13375  transforming growth factor beta-1
K04674  TGF-beta receptor type-1 [EC:2.7.11.30]
K04388  TGF-beta receptor type-2 [EC:2.7.11.30]
K04500  mothers against decapentaplegic homolog 2
K23605  mothers against decapentaplegic homolog 3
K04501  mothers against decapentaplegic homolog 4
K05434  interleukin 21
K05075  interleukin 21 receptor
K05070  interleukin 2 receptor gamma
K11217  Janus kinase 1 [EC:2.7.10.2]
K11218  Janus kinase 3 [EC:2.7.10.2]
K05405  interleukin 6
K05055  interleukin 6 receptor
K05060  interleukin 6 signal transducer
K04447  Janus kinase 2 [EC:2.7.10.2]
K05426  interleukin 23 subunit alpha
K05065  interleukin 23 receptor
K05063  interleukin 12 receptor beta-1
K11219  non-receptor tyrosine-protein kinase TYK2 [EC:2.7.10.2]
K04692  signal transducer and activator of transcription 3
K08534  RAR-related orphan receptor gamma
K08532  RAR-related orphan receptor alpha
K08268  hypoxia-inducible factor 1 alpha
K04079  molecular chaperone HtpG
K09093  aryl hydrocarbon receptor
K05489  interleukin 17A
K05494  interleukin 17F
K05445  interleukin 22
K06752  MHC class II antigen
K06454  T-cell surface glycoprotein CD4
K05856  lymphocyte cell-specific protein tyrosine kinase [EC:2.7.10.2]
K06451  T-cell surface glycoprotein CD3 epsilon chain
K06452  T-cell surface glycoprotein CD3 gamma chain
K10784  T cell receptor alpha chain V region
K10785  T-cell receptor beta chain V region
K06453  CD3Z antigen, zeta polypeptide
K06450  T-cell surface glycoprotein CD3 delta chain
K07360  tyrosine-protein kinase ZAP-70 [EC:2.7.10.2]
K07362  linker for activation of T cells family member 1
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17332  nuclear factor of activated T-cells, cytoplasmic 2
K17333  nuclear factor of activated T-cells, cytoplasmic 3
K18052  novel protein kinase C theta type [EC:2.7.11.13]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K04734  NF-kappa-B inhibitor alpha
K02581  NF-kappa-B inhibitor beta
K05872  NF-kappa-B inhibitor epsilon
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04379  proto-oncogene protein c-fos
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04448  transcription factor AP-1
K05430  interleukin 4
K05071  interleukin 4 receptor
K11225  signal transducer and activator of transcription 6
K17895  GATA-binding protein 3
K08367  runt-related transcription factor 1
K22629  interleukin 27 subunit alpha
K24476  interleukin 27 subunit beta
K19598  interleukin 27 receptor alpha
K04687  interferon gamma
K05132  interferon gamma receptor 1
K05133  interferon gamma receptor 2
K11220  signal transducer and activator of transcription 1
K10166  T-box protein 21
K05429  interleukin 2
K05068  interleukin 2 receptor alpha
K05069  interleukin 2 receptor beta
K11223  signal transducer and activator of transcription 5A
K11224  signal transducer and activator of transcription 5B
K10163  forkhead box P3
K08527  retinoic acid receptor alpha
K08524  retinoid X receptor alpha
K08525  retinoid X receptor beta
K08526  retinoid X receptor gamma
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
ko04010  MAPK signaling pathway
ko04020  Calcium signaling pathway
ko04064  NF-kappa B signaling pathway
ko04066  HIF-1 signaling pathway
ko04350  TGF-beta signaling pathway
ko04514  Cell adhesion molecules
ko04620  Toll-like receptor signaling pathway
ko04630  JAK-STAT signaling pathway
ko04660  T cell receptor signaling pathway
ko05321  Inflammatory bowel disease
ko05323  Rheumatoid arthritis

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Gene (87)   
   KEGG ORTHOLOGY (87)   
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