KEGG   PATHWAY: mna04659
Entry
mna04659                    Pathway                                
Name
Th17 cell differentiation - Miniopterus natalensis (Natal long-fingered bat)
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
mna04659  Th17 cell differentiation
mna04659

Other DBs
GO: 0072539
Organism
Miniopterus natalensis (Natal long-fingered bat) [GN:mna]
Gene
107528631  IL1B; interleukin-1 beta [KO:K04519]
107532712  IL1R1; interleukin-1 receptor type 1 isoform X1 [KO:K04386]
107527297  IL1RAP; interleukin-1 receptor accessory protein isoform X1 [KO:K04723]
107545565  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
107545613  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
107536041  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
107536051  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
107540994  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
107532119  IRF4; interferon regulatory factor 4 isoform X1 [KO:K09445]
107527735  interferon regulatory factor 4-like [KO:K09445]
107534176  TGFB1; transforming growth factor beta-1 [KO:K13375]
107544970  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
107526381  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
107546622  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
107525935  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
107546640  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
107529740  IL21; interleukin-21 [KO:K05434]
107539652  IL21R; interleukin-21 receptor [KO:K05075]
107532895  IL2RG; cytokine receptor common subunit gamma isoform X1 [KO:K05070]
107533604  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
107535380  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
107540295  IL6; interleukin-6 [KO:K05405]
107543721  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
107527134  IL6ST; interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
107538122  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
107546155  IL23A; interleukin-23 subunit alpha [KO:K05426]
107533896  IL23R; interleukin-23 receptor [KO:K05065]
107535370  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
107533300  TYK2; non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
107528938  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
107540772  RORC; nuclear receptor ROR-gamma isoform X1 [KO:K08534]
107533760  RORA; nuclear receptor ROR-alpha [KO:K08532]
107525927  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
107536915  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
107536502  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
107540327  AHR; aryl hydrocarbon receptor isoform X1 [KO:K09093]
107534654  IL17A; interleukin-17A [KO:K05489]
107534651  IL17F; interleukin-17F [KO:K05494]
107527220  IL22; interleukin-22 [KO:K05445]
107545174  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
107536419  DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
107544122  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
107542667  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
107542672  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
107542674  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
107545091  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
107545092  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
107544013  CD4; T-cell surface glycoprotein CD4 [KO:K06454]
107542423  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
107530780  CD3E; T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
107530779  CD3G; T-cell surface glycoprotein CD3 gamma chain [KO:K06452]
107531685  uncharacterized protein LOC107531685 [KO:K10784]
107529052  CD247; T-cell surface glycoprotein CD3 zeta chain [KO:K06453]
107530792  CD3D; T-cell surface glycoprotein CD3 delta chain [KO:K06450]
107543924  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
107541020  LAT; LOW QUALITY PROTEIN: linker for activation of T-cells family member 1 [KO:K07362]
107542131  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
107545505  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
107545813  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
107536108  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
107545969  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
107541561  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
107538236  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
107527885  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
107542460  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
107542599  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
107523913  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
107544156  IKBKG; NF-kappa-B essential modulator [KO:K07210]
107526117  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
107532199  NFKBIB; NF-kappa-B inhibitor beta isoform X1 [KO:K02581]
107536848  NFKBIE; NF-kappa-B inhibitor epsilon isoform X1 [KO:K05872]
107545508  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
107533544  RELA; transcription factor p65 [KO:K04735]
107541504  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
107530451  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
107533821  FOS; LOW QUALITY PROTEIN: proto-oncogene c-Fos [KO:K04379]
107537133  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
107527953  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
107528432  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
107536966  JUN; transcription factor AP-1 [KO:K04448]
107525027  IL4; interleukin-4 [KO:K05430]
107539670  interleukin-4 receptor subunit alpha-like [KO:K05071]
107544754  interleukin-4 receptor subunit alpha-like [KO:K05071]
107546227  STAT6; signal transducer and activator of transcription 6 isoform X1 [KO:K11225]
107542426  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
107533502  RUNX1; runt-related transcription factor 1 [KO:K08367]
107541003  IL27; interleukin-27 subunit alpha [KO:K22629]
107525739  EBI3; LOW QUALITY PROTEIN: interleukin-27 subunit beta [KO:K24476]
107544337  IL27RA; LOW QUALITY PROTEIN: interleukin-27 receptor subunit alpha [KO:K19598]
107527227  IFNG; interferon gamma [KO:K04687]
107530983  IFNGR1; interferon gamma receptor 1 [KO:K05132]
107537453  IFNGR2; interferon gamma receptor 2 [KO:K05133]
107540521  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
107528977  TBX21; T-box transcription factor TBX21 [KO:K10166]
107529760  IL2; interleukin-2 [KO:K05429]
107542420  IL2RA; interleukin-2 receptor subunit alpha [KO:K05068]
107545294  IL2RB; interleukin-2 receptor subunit beta [KO:K05069]
107528939  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
107528845  signal transducer and activator of transcription 5B-like [KO:K11224]
107541386  FOXP3; forkhead box protein P3 isoform X1 [KO:K10163]
107528992  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
107524613  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
107542678  RXRB; retinoic acid receptor RXR-beta [KO:K08525]
107537950  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
mna04010  MAPK signaling pathway
mna04020  Calcium signaling pathway
mna04064  NF-kappa B signaling pathway
mna04066  HIF-1 signaling pathway
mna04350  TGF-beta signaling pathway
mna04514  Cell adhesion molecules
mna04620  Toll-like receptor signaling pathway
mna04630  JAK-STAT signaling pathway
mna04660  T cell receptor signaling pathway
mna05321  Inflammatory bowel disease
mna05323  Rheumatoid arthritis
KO pathway
ko04659   
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