KEGG   PATHWAY: mcf04659
Entry
mcf04659                    Pathway                                
Name
Th17 cell differentiation - Macaca fascicularis (crab-eating macaque)
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
mcf04659  Th17 cell differentiation
mcf04659

Other DBs
GO: 0072539
Organism
Macaca fascicularis (crab-eating macaque) [GN:mcf]
Gene
102119749  IL1B; interleukin-1 beta [KO:K04519]
102146317  IL1R1; interleukin-1 receptor type 1 [KO:K04386]
102133222  interleukin-1 receptor accessory protein isoform X2 [KO:K04723]
101867352  MAPK13; mitogen-activated protein kinase 13 isoform X2 [KO:K04441] [EC:2.7.11.24]
101926770  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102134421  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
101867305  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
102128371  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102132399  IRF4; interferon regulatory factor 4 isoform X1 [KO:K09445]
102129546  TGFB1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
102115287  TGFBR1; TGF-beta receptor type-1 isoform X3 [KO:K04674] [EC:2.7.11.30]
102134273  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
101925163  SMAD2; mothers against decapentaplegic homolog 2 isoform X5 [KO:K04500]
102146086  SMAD3; mothers against decapentaplegic homolog 3 isoform X2 [KO:K23605]
102142438  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
102130762  IL21; interleukin-21 [KO:K05434]
102135042  IL21R; interleukin-21 receptor [KO:K05075]
102144912  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
102123983  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
102134669  JAK3; tyrosine-protein kinase JAK3 isoform X1 [KO:K11218] [EC:2.7.10.2]
102138971  IL6; interleukin-6 precursor [KO:K05405]
102117292  IL6R; LOW QUALITY PROTEIN: interleukin-6 receptor subunit alpha [KO:K05055]
101926138  IL6ST; interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
102119008  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
102128555  IL23A; interleukin-23 subunit alpha [KO:K05426]
102133210  IL23R; interleukin-23 receptor [KO:K05065]
102143359  IL12RB1; interleukin-12 receptor subunit beta-1 isoform X1 [KO:K05063]
102143094  TYK2; non-receptor tyrosine-protein kinase TYK2 isoform X1 [KO:K11219] [EC:2.7.10.2]
102118402  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
102145834  RORC; nuclear receptor ROR-gamma isoform X4 [KO:K08534]
102142259  RORA; nuclear receptor ROR-alpha isoform X3 [KO:K08532]
101866092  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
101926380  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
102123807  LOW QUALITY PROTEIN: heat shock protein HSP 90-alpha-like [KO:K04079]
101866865  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
102129171  AHR; aryl hydrocarbon receptor [KO:K09093]
102119976  IL17A; interleukin-17A [KO:K05489]
102118959  IL17F; interleukin-17F [KO:K05494]
102129310  IL22; interleukin-22 [KO:K05445]
102136468  HLA class II histocompatibility antigen, DP beta 1 chain isoform X1 [KO:K06752]
102137481  HLA class II histocompatibility antigen, DO alpha chain isoform X1 [KO:K06752]
102140649  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
102139994  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
102145413  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
102132662  HLA class II histocompatibility antigen, DQ alpha 2 chain [KO:K06752]
102144414  HLA class II histocompatibility antigen, DR beta 5 chain isoform X1 [KO:K06752]
102144039  mamu class II histocompatibility antigen, DR alpha chain [KO:K06752]
102136862  HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
102133044  HLA class II histocompatibility antigen, DQ beta 1 chain isoform X1 [KO:K06752]
123572852  H-2 class II histocompatibility antigen, A-D alpha chain-like [KO:K06752]
123572854  class II histocompatibility antigen, B-L beta chain-like [KO:K06752]
123572909  mamu class II histocompatibility antigen, DR alpha chain-like [KO:K06752]
101864991  CD4; T-cell surface glycoprotein CD4 [KO:K06454]
102140916  LCK; tyrosine-protein kinase Lck isoform X1 [KO:K05856] [EC:2.7.10.2]
102133065  CD3E; T-cell surface glycoprotein CD3 epsilon chain isoform X1 [KO:K06451]
102134381  CD3G; T-cell surface glycoprotein CD3 gamma chain isoform X1 [KO:K06452]
102118501  CD247; T-cell surface glycoprotein CD3 zeta chain isoform X1 [KO:K06453]
102133701  CD3D; T-cell surface glycoprotein CD3 delta chain isoform X3 [KO:K06450]
102135442  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
102143768  LAT; linker for activation of T-cells family member 1 isoform X1 [KO:K07362]
102138726  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
101926738  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
102134477  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
101866070  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
102137250  PPP3R1; calcineurin subunit B type 1 isoform X1 [KO:K06268]
101866439  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
102133233  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446]
102136960  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
102136724  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
102125438  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
102115964  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
102146604  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
102115368  IKBKG; NF-kappa-B essential modulator isoform X5 [KO:K07210]
101867458  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
102130059  NFKBIB; NF-kappa-B inhibitor beta isoform X2 [KO:K02581]
102130086  NFKBIE; NF-kappa-B inhibitor epsilon [KO:K05872]
102138273  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101867324  RELA; transcription factor p65 isoform X1 [KO:K04735]
102145011  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102116996  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
102143716  FOS; proto-oncogene c-Fos [KO:K04379]
102118497  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102126339  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102121272  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102126446  JUN; transcription factor AP-1 [KO:K04448]
107130068  IL4; interleukin-4 [KO:K05430]
102133649  IL4R; interleukin-4 receptor subunit alpha isoform X1 [KO:K05071]
102117594  STAT6; signal transducer and activator of transcription 6 isoform X1 [KO:K11225]
102135253  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
102145008  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
102145935  IL27; interleukin-27 subunit alpha [KO:K22629]
102144621  EBI3; interleukin-27 subunit beta [KO:K24476]
102139216  IL27RA; interleukin-27 receptor subunit alpha isoform X1 [KO:K19598]
102128291  IFNG; interferon gamma [KO:K04687]
101866179  IFNGR1; interferon gamma receptor 1 isoform X3 [KO:K05132]
102138221  IFNGR2; interferon gamma receptor 2 [KO:K05133]
101925134  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
102141237  TBX21; T-box transcription factor TBX21 [KO:K10166]
102129830  IL2; interleukin-2 [KO:K05429]
102123605  IL2RA; interleukin-2 receptor subunit alpha isoform X1 [KO:K05068]
102138714  IL2RB; interleukin-2 receptor subunit beta isoform X1 [KO:K05069]
102120556  signal transducer and activator of transcription 5A [KO:K11223]
102127060  signal transducer and activator of transcription 5B [KO:K11224]
102120882  FOXP3; forkhead box protein P3 isoform X2 [KO:K10163]
102132722  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
102133330  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
102132522  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
101864810  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
mcf04010  MAPK signaling pathway
mcf04020  Calcium signaling pathway
mcf04064  NF-kappa B signaling pathway
mcf04066  HIF-1 signaling pathway
mcf04350  TGF-beta signaling pathway
mcf04514  Cell adhesion molecules
mcf04620  Toll-like receptor signaling pathway
mcf04630  JAK-STAT signaling pathway
mcf04660  T cell receptor signaling pathway
mcf05321  Inflammatory bowel disease
mcf05323  Rheumatoid arthritis
KO pathway
ko04659   
LinkDB

DBGET integrated database retrieval system