KEGG   PATHWAY: dnm04659
Entry
dnm04659                    Pathway                                
Name
Th17 cell differentiation - Dasypus novemcinctus (nine-banded armadillo)
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
dnm04659  Th17 cell differentiation
dnm04659

Other DBs
GO: 0072539
Organism
Dasypus novemcinctus (nine-banded armadillo) [GN:dnm]
Gene
101445167  IL1B; interleukin-1 beta [KO:K04519]
101447218  IL1R1; interleukin-1 receptor type 1 isoform X1 [KO:K04386]
101442775  IL1RAP; interleukin-1 receptor accessory protein isoform X3 [KO:K04723]
101425795  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101426841  MAPK13; mitogen-activated protein kinase 13 isoform X2 [KO:K04441] [EC:2.7.11.24]
101415496  MAPK12; mitogen-activated protein kinase 12 isoform X2 [KO:K04441] [EC:2.7.11.24]
101416217  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
101434069  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101433182  interferon regulatory factor 4-like [KO:K09445]
101432765  IRF4; interferon regulatory factor 4 [KO:K09445]
101437737  TGFB1; transforming growth factor beta-1 [KO:K13375]
101411588  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
101430016  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
101429090  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
101447050  SMAD3; mothers against decapentaplegic homolog 3 isoform X2 [KO:K23605]
101427870  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
101412897  IL21; interleukin-21 [KO:K05434]
101427503  IL21R; interleukin-21 receptor [KO:K05075]
101437298  IL2RG; cytokine receptor common subunit gamma isoform X1 [KO:K05070]
101432776  JAK1; LOW QUALITY PROTEIN: tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
101430345  tyrosine-protein kinase JAK3-like [KO:K11218] [EC:2.7.10.2]
101429481  LOW QUALITY PROTEIN: interleukin-6-like [KO:K05405]
101443963  IL6; interleukin-6 [KO:K05405]
101421663  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
101441436  IL6ST; interleukin-6 receptor subunit beta [KO:K05060]
101416389  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
101423062  IL23A; LOW QUALITY PROTEIN: interleukin-23 subunit alpha [KO:K05426]
101417062  IL23R; interleukin-23 receptor [KO:K05065]
101432301  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
101428688  TYK2; LOW QUALITY PROTEIN: non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
101444225  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
101438223  RORC; nuclear receptor ROR-gamma isoform X1 [KO:K08534]
101447163  RORA; nuclear receptor ROR-alpha isoform X2 [KO:K08532]
101443806  HIF1A; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
101442872  heat shock protein HSP 90-alpha A2 [KO:K04079]
101414308  AHR; aryl hydrocarbon receptor [KO:K09093]
101423034  IL17A; interleukin-17A [KO:K05489]
101419515  IL17F; interleukin-17F [KO:K05494]
101421986  IL22; interleukin-22 [KO:K05445]
101415145  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
101437028  LOW QUALITY PROTEIN: DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
101443412  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DRB1-4 beta chain-like [KO:K06752]
101438478  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
101440773  HLA class II histocompatibility antigen, DQ beta 2 chain-like [KO:K06752]
101433781  HLA class II histocompatibility antigen, DO beta chain isoform X1 [KO:K06752]
101435501  HLA class II histocompatibility antigen, DQ alpha 1 chain-like [KO:K06752]
101435917  HLA class II histocompatibility antigen, DQ alpha 2 chain-like isoform X1 [KO:K06752]
101436345  DLA class II histocompatibility antigen, DR-1 beta chain-like isoform X1 [KO:K06752]
101437751  HLA class II histocompatibility antigen, DRB1-4 beta chain-like [KO:K06752]
101415573  HLA class II histocompatibility antigen, DP beta 1 chain-like isoform X1 [KO:K06752]
101417015  HLA class II histocompatibility antigen, DP alpha 1 chain isoform X1 [KO:K06752]
101417743  HLA class II histocompatibility antigen, DO alpha chain isoform X1 [KO:K06752]
101421271  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
101421706  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
101411381  CD4; T-cell surface glycoprotein CD4 isoform X1 [KO:K06454]
101445129  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
101421796  CD3E; T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
101412450  CD3G; T-cell surface glycoprotein CD3 gamma chain isoform X1 [KO:K06452]
101425248  CD247; T-cell surface glycoprotein CD3 zeta chain isoform X1 [KO:K06453]
101413471  CD3D; T-cell surface glycoprotein CD3 delta chain [KO:K06450]
101423099  tyrosine-protein kinase ZAP-70 isoform X1 [KO:K07360] [EC:2.7.10.2]
101417876  LAT; linker for activation of T-cells family member 1 [KO:K07362]
101411498  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
101435854  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
101420075  PPP3CC; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16]
101427629  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
101440970  calcineurin subunit B type 2 [KO:K06268]
101427882  NFATC1; LOW QUALITY PROTEIN: nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
101417008  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
101424450  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333]
101410614  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
101429772  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
101411204  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101439489  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
101412730  NFKBIA; LOW QUALITY PROTEIN: NF-kappa-B inhibitor alpha [KO:K04734]
101425701  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
101437556  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
101417885  RELA; transcription factor p65 [KO:K04735]
101430570  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101435742  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101431782  FOS; proto-oncogene c-Fos [KO:K04379]
101423710  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
101416102  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101421932  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101412001  JUN; transcription factor AP-1 [KO:K04448]
101420628  IL4; interleukin-4 [KO:K05430]
101433800  IL4R; interleukin-4 receptor subunit alpha [KO:K05071]
101445221  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
101422753  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
101443635  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
101447686  IL27; interleukin-27 subunit alpha [KO:K22629]
101425539  EBI3; interleukin-27 subunit beta [KO:K24476]
101447393  IL27RA; LOW QUALITY PROTEIN: interleukin-27 receptor subunit alpha [KO:K19598]
101422877  IFNG; interferon gamma [KO:K04687]
101416634  IFNGR1; interferon gamma receptor 1 [KO:K05132]
101425494  IFNGR2; interferon gamma receptor 2 [KO:K05133]
101436399  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
101413757  IL2; interleukin-2 precursor [KO:K05429]
101410814  IL2RA; interleukin-2 receptor subunit alpha [KO:K05068]
101440447  IL2RB; interleukin-2 receptor subunit beta [KO:K05069]
101443775  STAT5A; signal transducer and activator of transcription 5A isoform X2 [KO:K11223]
101419007  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
101446573  FOXP3; forkhead box protein P3 [KO:K10163]
101433218  RARA; retinoic acid receptor alpha [KO:K08527]
101411907  RXRA; retinoic acid receptor RXR-alpha isoform X2 [KO:K08524]
101414688  RXRB; LOW QUALITY PROTEIN: retinoic acid receptor RXR-beta [KO:K08525]
101428198  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
dnm04010  MAPK signaling pathway
dnm04020  Calcium signaling pathway
dnm04064  NF-kappa B signaling pathway
dnm04066  HIF-1 signaling pathway
dnm04350  TGF-beta signaling pathway
dnm04514  Cell adhesion molecules
dnm04620  Toll-like receptor signaling pathway
dnm04630  JAK-STAT signaling pathway
dnm04660  T cell receptor signaling pathway
dnm05321  Inflammatory bowel disease
dnm05323  Rheumatoid arthritis
KO pathway
ko04659   
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