KEGG   PATHWAY: mcc04659
Entry
mcc04659                    Pathway                                
Name
Th17 cell differentiation - Macaca mulatta (rhesus monkey)
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
mcc04659  Th17 cell differentiation
mcc04659

Other DBs
GO: 0072539
Organism
Macaca mulatta (rhesus monkey) [GN:mcc]
Gene
704701  IL1B; interleukin-1 beta precursor [KO:K04519]
711726  IL1R1; interleukin-1 receptor type 1 [KO:K04386]
574387  IL1RAP; interleukin-1 receptor accessory protein precursor [KO:K04723]
715745  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
715794  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
718976  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
719085  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
106992736  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
722883  IRF4; interferon regulatory factor 4 [KO:K09445]
106992315  TGFB1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
714952  TGFBR1; TGF-beta receptor type-1 isoform X2 [KO:K04674] [EC:2.7.11.30]
703088  TGFBR2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]
114675335  LOW QUALITY PROTEIN: TGF-beta receptor type-2-like [KO:K04388] [EC:2.7.11.30]
697581  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
711355  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
701803  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
708125  IL21; interleukin-21 precursor [KO:K05434]
705759  IL21R; interleukin-21 receptor [KO:K05075]
641338  IL2RG; cytokine receptor common subunit gamma precursor [KO:K05070]
677689  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
720040  JAK3; LOW QUALITY PROTEIN: tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
114669853  LOW QUALITY PROTEIN: tyrosine-protein kinase JAK3-like [KO:K11218] [EC:2.7.10.2]
705819  IL6; interleukin-6 precursor [KO:K05405]
716690  IL6R; interleukin-6 receptor subunit alpha isoform X2 [KO:K05055]
574127  IL6ST; interleukin-6 receptor subunit beta precursor [KO:K05060]
694184  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
712627  IL23A; interleukin-23 subunit alpha precursor [KO:K05426]
700440  IL23R; interleukin-23 receptor [KO:K05065]
574199  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
574130  TYK2; non-receptor tyrosine-protein kinase TYK2 isoform X1 [KO:K11219] [EC:2.7.10.2]
574128  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
717052  RORC; nuclear receptor ROR-gamma isoform X1 [KO:K08534]
704014  RORA; nuclear receptor ROR-alpha isoform X2 [KO:K08532]
704678  HIF1A; hypoxia-inducible factor 1-alpha isoform X4 [KO:K08268]
702293  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
708431  HSP90AA1; heat shock protein 90kDa alpha (cytosolic), class A member 1 [KO:K04079]
714254  AHR; aryl hydrocarbon receptor [KO:K09093]
100423621  aryl hydrocarbon receptor-like isoform X1 [KO:K09093]
708123  IL17A; interleukin-17A [KO:K05489]
708220  IL17F; interleukin-17F precursor [KO:K05494]
718047  IL22; interleukin-22 precursor [KO:K05445]
692100  MAMU-DRB1; major histocompatibility complex, class II, DR beta 1 precursor [KO:K06752]
717870  MAMU-DMA; major histocompatibility complex, class II, DM alpha precursor [KO:K06752]
717969  MAMU-DPB; major histocompatibility complex, class II, DP beta [KO:K06752]
717947  MAMU-DOA; major histocompatibility complex, class II, DO alpha precursor [KO:K06752]
717992  MAMU-DPA; major histocompatibility complex, class II, DP alpha [KO:K06752]
717702  MAMU-DOB; major histocompatibility complex, class II, DO beta precursor [KO:K06752]
100187587  MAMU-DRA; mamu class II histocompatibility antigen, DR alpha chain precursor [KO:K06752]
720582  MAMU-DQA1; major histocompatibility complex, class II, DQ alpha 1 precursor [KO:K06752]
716823  MAMU-DQB1; major histocompatibility complex, class II, DQ beta 1 precursor [KO:K06752]
100429857  MAMU-DMB; major histocompatibility complex, class II, DM beta precursor [KO:K06752]
100428228  MAMU-DRB5; LOW QUALITY PROTEIN: MHC class II antigen, Mamu-DRB5 [KO:K06752]
100428435  HLA class II histocompatibility antigen, DRB1-3 chain [KO:K06752]
114669810  HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
114675357  HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
106997902  DLA class II histocompatibility antigen, DR-1 beta chain-like isoform X1 [KO:K06752]
713807  CD4; T-cell surface glycoprotein CD4 precursor [KO:K06454]
717704  LCK; tyrosine-protein kinase Lck isoform X1 [KO:K05856] [EC:2.7.10.2]
699467  CD3E; T-cell surface glycoprotein CD3 epsilon chain isoform X1 [KO:K06451]
705270  CD3G; T-cell surface glycoprotein CD3 gamma chain precursor [KO:K06452]
710149  uncharacterized protein LOC710149 [KO:K10784]
698785  LOW QUALITY PROTEIN: uncharacterized protein LOC698785 [KO:K10785]
696306  T cell receptor beta variable 3-1 [KO:K10785]
697904  uncharacterized protein LOC697904 [KO:K10785]
703029  immunoglobulin lambda-1 light chain-like [KO:K10785]
697814  CD247; T-cell surface glycoprotein CD3 zeta chain precursor [KO:K06453]
699582  CD3D; T-cell surface glycoprotein CD3 delta chain isoform X1 [KO:K06450]
707555  tyrosine-protein kinase ZAP-70 isoform X1 [KO:K07360] [EC:2.7.10.2]
704656  LAT; linker for activation of T-cells family member 1 isoform X2 [KO:K07362]
697069  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
706955  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X7 [KO:K04348] [EC:3.1.3.16]
708233  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X2 [KO:K04348] [EC:3.1.3.16]
709773  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16]
574258  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
100428682  PPP3R1; calcineurin subunit B type 1 isoform X3 [KO:K06268]
698089  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X2 [KO:K04446]
710601  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
702390  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333]
722559  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
709511  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X3 [KO:K04467] [EC:2.7.11.10]
704683  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
701237  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
695335  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
694844  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
702498  NFKBIE; LOW QUALITY PROTEIN: NF-kappa-B inhibitor epsilon [KO:K05872]
710324  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
715919  RELA; transcription factor p65 isoform X1 [KO:K04735]
708938  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
698569  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
702077  FOS; proto-oncogene c-Fos [KO:K04379]
699736  MAPK10; mitogen-activated protein kinase 10 isoform 1 [KO:K04440] [EC:2.7.11.24]
711115  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
715782  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
716452  JUN; transcription factor AP-1 [KO:K04448]
574281  IL4; interleukin-4 precursor [KO:K05430]
705404  IL4R; interleukin-4 receptor subunit alpha isoform X2 [KO:K05071]
714159  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
713840  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
696749  RUNX1; runt-related transcription factor 1 [KO:K08367]
708678  IL27; interleukin-27 subunit alpha [KO:K22629]
721832  EBI3; interleukin-27 subunit beta [KO:K24476]
717549  IL27RA; interleukin-27 receptor subunit alpha [KO:K19598]
574282  IFNG; interferon gamma precursor [KO:K04687]
100423877  IFNGR1; interferon gamma receptor 1 precursor [KO:K05132]
699489  IFNGR2; interferon gamma receptor 2 [KO:K05133]
693650  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
694044  TBX21; T-box transcription factor TBX21 [KO:K10166]
708017  IL2; interleukin-2 precursor [KO:K05429]
574300  IL2RA; interleukin-2 receptor subunit alpha precursor [KO:K05068]
696331  IL2RB; interleukin-2 receptor subunit beta precursor [KO:K05069]
574129  STAT5A; signal transducer and activator of transcription 5A isoform 2 [KO:K11223]
709760  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
574303  FOXP3; forkhead box protein P3 [KO:K10163]
700206  RARA; retinoic acid receptor alpha isoform X2 [KO:K08527]
722068  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
717368  RXRB; retinoic acid receptor RXR-beta isoform X2 [KO:K08525]
694807  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
mcc04010  MAPK signaling pathway
mcc04020  Calcium signaling pathway
mcc04064  NF-kappa B signaling pathway
mcc04066  HIF-1 signaling pathway
mcc04350  TGF-beta signaling pathway
mcc04514  Cell adhesion molecules
mcc04620  Toll-like receptor signaling pathway
mcc04630  JAK-STAT signaling pathway
mcc04660  T cell receptor signaling pathway
mcc05321  Inflammatory bowel disease
mcc05323  Rheumatoid arthritis
KO pathway
ko04659   
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