KEGG   PATHWAY: ocu04659
Entry
ocu04659                    Pathway                                
Name
Th17 cell differentiation - Oryctolagus cuniculus (rabbit)
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
ocu04659  Th17 cell differentiation
ocu04659

Other DBs
GO: 0072539
Organism
Oryctolagus cuniculus (rabbit) [GN:ocu]
Gene
100008990  IL1B; interleukin-1 beta precursor [KO:K04519]
100352905  interleukin-1 receptor type 1 isoform X1 [KO:K04386]
100341281  interleukin-1 receptor accessory protein isoform X3 [KO:K04723]
100341695  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100344161  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100350614  mitogen-activated protein kinase 12 isoform X2 [KO:K04441] [EC:2.7.11.24]
103346035  mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
100356164  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100349109  interferon regulatory factor 4 isoform X1 [KO:K09445]
100008645  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
100352301  LOW QUALITY PROTEIN: transforming growth factor beta-1 proprotein [KO:K13375]
103345448  transforming growth factor beta-1 proprotein isoform X9 [KO:K13375]
100345812  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100344335  TGFBR2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]
100359137  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100346303  mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
100342294  mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
100344172  interleukin-21 [KO:K05434]
103348594  interleukin-21 receptor [KO:K05075]
103351862  cytokine receptor common subunit gamma [KO:K05070]
100352594  tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
127486194  tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
100008733  IL6; interleukin-6 precursor [KO:K05405]
100347752  interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
100349330  interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
100358134  tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
100352065  interleukin-23 subunit alpha [KO:K05426]
127487391  interleukin-23 subunit alpha-like [KO:K05426]
100350917  interleukin-23 receptor [KO:K05065]
100344622  non-receptor tyrosine-protein kinase TYK2 isoform X1 [KO:K11219] [EC:2.7.10.2]
100348778  signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
100353540  nuclear receptor ROR-gamma [KO:K08534]
100357159  nuclear receptor ROR-alpha isoform X3 [KO:K08532]
100009579  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
100338694  heat shock protein HSP 90-alpha [KO:K04079]
100358690  heat shock protein HSP 90-beta [KO:K04079]
100008995  AHR; aryl hydrocarbon receptor [KO:K09093]
100358544  aryl hydrocarbon receptor [KO:K09093]
100339322  interleukin-17A [KO:K05489]
100339570  interleukin-17F [KO:K05494]
100348980  interleukin-22 [KO:K05445]
100328929  RLA-DR-ALPHA; major histocompatibility complex, class II, DR alpha precursor [KO:K06752]
100341358  RLA class II histocompatibility antigen, DP beta chain isoform X1 [KO:K06752]
100343144  HLA class II histocompatibility antigen, DQ alpha 1 chain [KO:K06752]
100349408  H-2 class II histocompatibility antigen, E-S beta chain [KO:K06752]
100349667  HLA class II histocompatibility antigen, DRB1 beta chain [KO:K06752]
100350168  HLA class II histocompatibility antigen, DRB1 beta chain isoform X1 [KO:K06752]
100350656  RLA-DRB1; HLA class II histocompatibility antigen, DRB1 beta chain [KO:K06752]
100351163  HLA class II histocompatibility antigen, DQ beta 1 chain [KO:K06752]
100351416  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
100352415  RLA-DMA; histocompatibility antigen DM heterodimer heavy chain-like precursor [KO:K06752]
100352672  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
100352927  RLA class II histocompatibility antigen, DP alpha-1 chain isoform X2 [KO:K06752]
100355948  RLA-DMB; histocompatibility antigen DM heterodimer light chain-like precursor [KO:K06752]
127482571  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
100009152  CD4; T-cell surface glycoprotein CD4 precursor [KO:K06454]
100349102  tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
100008616  CD3E; T-cell surface glycoprotein CD3 epsilon chain precursor [KO:K06451]
100339529  T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
100352809  T-cell surface glycoprotein CD3 gamma chain isoform X1 [KO:K06452]
100355340  T-cell surface glycoprotein CD3 gamma chain isoform X1 [KO:K06452]
108178285  uncharacterized protein LOC108178285 [KO:K10784]
100008617  CD247; T-cell surface glycoprotein CD3 zeta chain precursor [KO:K06453]
100356153  T-cell surface glycoprotein CD3 delta chain isoform X1 [KO:K06450]
100342021  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
100350076  linker for activation of T-cells family member 1 isoform X2 [KO:K07362]
100349958  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100009423  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
100009487  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:3.1.3.16]
100356245  serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
100344533  calcineurin subunit B type 2 [KO:K06268]
100352378  nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
100353824  nuclear factor of activated T-cells, cytoplasmic 2 isoform X3 [KO:K17332]
100008859  nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333]
103350889  protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
100355888  inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
100356401  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X5 [KO:K07209] [EC:2.7.11.10]
100328905  IKBKG; NF-kappa-B essential modulator [KO:K07210]
100357341  NF-kappa-B inhibitor alpha [KO:K04734]
100359283  NF-kappa-B inhibitor beta isoform X2 [KO:K02581]
100359054  NF-kappa-B inhibitor epsilon [KO:K05872]
100349426  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
127485184  transcription factor p65 isoform X1 [KO:K04735]
100347345  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100348561  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100338345  protein c-Fos [KO:K04379]
100337999  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100342664  mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
100346929  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100008856  JUN; transcription factor Jun [KO:K04448]
100302454  IL4; interleukin-4 isoform 1 precursor [KO:K05430]
100337721  interleukin-4 receptor subunit alpha [KO:K05071]
100344264  signal transducer and activator of transcription 6 [KO:K11225]
100347169  trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
100358993  runt-related transcription factor 1 isoform X1 [KO:K08367]
100349321  interleukin-27 subunit alpha [KO:K22629]
103347059  interleukin-27 receptor subunit alpha isoform X1 [KO:K19598]
100008602  IFNG; interferon gamma precursor [KO:K04687]
100341787  interferon gamma receptor 1 isoform X1 [KO:K05132]
100338854  interferon gamma receptor 2 [KO:K05133]
100343893  signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
127488928  signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100350283  T-box transcription factor TBX21 [KO:K10166]
100302458  IL2; interleukin-2 isoform 1 precursor [KO:K05429]
100338113  interleukin-2 receptor subunit alpha [KO:K05068]
100358489  interleukin-2 receptor subunit alpha [KO:K05068]
103346218  interleukin-2 receptor subunit beta [KO:K05069]
100348518  signal transducer and activator of transcription 5A [KO:K11223]
100348267  signal transducer and activator of transcription 5B [KO:K11224]
100348270  forkhead box protein P3 isoform X1 [KO:K10163]
100009009  retinoic acid receptor alpha isoform X3 [KO:K08527]
100354287  retinoic acid receptor RXR-beta isoform X2 [KO:K08525]
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
ocu04010  MAPK signaling pathway
ocu04020  Calcium signaling pathway
ocu04064  NF-kappa B signaling pathway
ocu04066  HIF-1 signaling pathway
ocu04350  TGF-beta signaling pathway
ocu04514  Cell adhesion molecules
ocu04620  Toll-like receptor signaling pathway
ocu04630  JAK-STAT signaling pathway
ocu04660  T cell receptor signaling pathway
ocu05321  Inflammatory bowel disease
ocu05323  Rheumatoid arthritis
KO pathway
ko04659   
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