KEGG   PATHWAY: hsa04658
Entry
hsa04658                    Pathway                                
Name
Th1 and Th2 cell differentiation - Homo sapiens (human)
Description
Immunity to different classes of microorganisms is orchestrated by separate lineages of effector T helper (TH)-cells, which differentiate from naive CD4+ precursor cells in response to cues provided by antigen presenting cells (APC) and include T helper type 1 (Th1) and Th2. Th1 cells are characterized by the transcription factor T-bet and signal transducer and activator of transcription (STAT) 4, and the production of IFN-gamma. These cells stimulate strong cell-mediated immune responses, particularly against intracellular pathogens. On the other hand, transcription factors like GATA-3 and STAT6 drive the generation of Th2 cells that produce IL-4, IL-5 and IL-13 and are necessary for inducing the humoral response to combat parasitic helminths (type 2 immunity) and isotype switching to IgG1 and IgE. The balance between Th1/Th2 subsets determines the susceptibility to disease states, where the improper development of Th2 cells can lead to allergy, while an overactive Th1 response can lead to autoimmunity.
Class
Organismal Systems; Immune system
Pathway map
hsa04658  Th1 and Th2 cell differentiation
hsa04658

Drug
D00107  Tacrolimus (USP/INN)
D00184  Cyclosporine (USP)
D05092  Muromonab-CD3 (JAN/USAN/INN)
D05480  Pimecrolimus (JAN/USAN/INN)
D08556  Tacrolimus (INN)
D09013  Teplizumab (USAN/INN)
D09033  Voclosporin (JAN/USAN/INN)
D09190  Anti-human thymocyte immunoglobulin, rabbit (JAN)
D10871  Filgotinib (USAN/INN)
D10872  Filgotinib hydrochloride (USAN)
D10981  Rovalpituzumab tesirine (USAN/INN)
D11046  Delgocitinib (JAN/USAN/INN)
D11106  Filgotinib maleate (JAN/USAN)
D11117  Rovalpituzumab (USAN)
D11400  Abrocitinib (JAN/USAN)
D11537  Brepocitinib (USAN)
D11538  Brepocitinib tosylate (USAN)
D11817  Deucravacitinib (JAN/USAN)
D12118  Nezulcitinib (USAN)
D12211  Ivarmacitinib (USAN)
D12212  Ivarmacitinib sulfate (USAN)
D12368  Epcoritamab (USAN/INN)
Other DBs
GO: 0045063 0045064
Organism
Homo sapiens (human) [GN:hsa]
Gene
10683  DLL3; delta like canonical Notch ligand 3 [KO:K06051]
28514  DLL1; delta like canonical Notch ligand 1 [KO:K06051]
54567  DLL4; delta like canonical Notch ligand 4 [KO:K06051]
4854  NOTCH3; notch receptor 3 [KO:K20995]
55534  MAML3; mastermind like transcriptional coactivator 3 [KO:K06061]
84441  MAML2; mastermind like transcriptional coactivator 2 [KO:K06061]
9794  MAML1; mastermind like transcriptional coactivator 1 [KO:K06061]
11317  RBPJL; recombination signal binding protein for immunoglobulin kappa J region like [KO:K06053]
3516  RBPJ; recombination signal binding protein for immunoglobulin kappa J region [KO:K06053]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
3458  IFNG; interferon gamma [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 [KO:K05133]
3716  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
3592  IL12A; interleukin 12A [KO:K05406]
3593  IL12B; interleukin 12B [KO:K05425]
3594  IL12RB1; interleukin 12 receptor subunit beta 1 [KO:K05063]
3595  IL12RB2; interleukin 12 receptor subunit beta 2 [KO:K05064]
7297  TYK2; tyrosine kinase 2 [KO:K11219] [EC:2.7.10.2]
6775  STAT4; signal transducer and activator of transcription 4 [KO:K11222]
30009  TBX21; T-box transcription factor 21 [KO:K10166]
864  RUNX3; RUNX family transcription factor 3 [KO:K09279]
3108  HLA-DMA; major histocompatibility complex, class II, DM alpha [KO:K06752]
3109  HLA-DMB; major histocompatibility complex, class II, DM beta [KO:K06752]
3111  HLA-DOA; major histocompatibility complex, class II, DO alpha [KO:K06752]
3112  HLA-DOB; major histocompatibility complex, class II, DO beta [KO:K06752]
3113  HLA-DPA1; major histocompatibility complex, class II, DP alpha 1 [KO:K06752]
3115  HLA-DPB1; major histocompatibility complex, class II, DP beta 1 [KO:K06752]
3117  HLA-DQA1; major histocompatibility complex, class II, DQ alpha 1 [KO:K06752]
3118  HLA-DQA2; major histocompatibility complex, class II, DQ alpha 2 [KO:K06752]
3119  HLA-DQB1; major histocompatibility complex, class II, DQ beta 1 [KO:K06752]
3122  HLA-DRA; major histocompatibility complex, class II, DR alpha [KO:K06752]
3123  HLA-DRB1; major histocompatibility complex, class II, DR beta 1 [KO:K06752]
3125  HLA-DRB3; major histocompatibility complex, class II, DR beta 3 [KO:K06752]
3126  HLA-DRB4; major histocompatibility complex, class II, DR beta 4 [KO:K06752]
3127  HLA-DRB5; major histocompatibility complex, class II, DR beta 5 [KO:K06752]
920  CD4; CD4 molecule [KO:K06454]
3932  LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
916  CD3E; CD3 epsilon subunit of T-cell receptor complex [KO:K06451]
917  CD3G; CD3 gamma subunit of T-cell receptor complex [KO:K06452]
919  CD247; CD247 molecule [KO:K06453]
915  CD3D; CD3 delta subunit of T-cell receptor complex [KO:K06450]
7535  ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360] [EC:2.7.10.2]
27040  LAT; linker for activation of T cells [KO:K07362]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
5532  PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
5533  PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
5534  PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
5535  PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268]
4772  NFATC1; nuclear factor of activated T cells 1 [KO:K04446]
4773  NFATC2; nuclear factor of activated T cells 2 [KO:K17332]
4775  NFATC3; nuclear factor of activated T cells 3 [KO:K17333]
5588  PRKCQ; protein kinase C theta [KO:K18052] [EC:2.7.11.13]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4793  NFKBIB; NFKB inhibitor beta [KO:K02581]
4794  NFKBIE; NFKB inhibitor epsilon [KO:K05872]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
3558  IL2; interleukin 2 [KO:K05429]
3559  IL2RA; interleukin 2 receptor subunit alpha [KO:K05068]
3560  IL2RB; interleukin 2 receptor subunit beta [KO:K05069]
3561  IL2RG; interleukin 2 receptor subunit gamma [KO:K05070]
3718  JAK3; Janus kinase 3 [KO:K11218] [EC:2.7.10.2]
6776  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
6777  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
3565  IL4; interleukin 4 [KO:K05430]
3566  IL4R; interleukin 4 receptor [KO:K05071]
6778  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
2625  GATA3; GATA binding protein 3 [KO:K17895]
3567  IL5; interleukin 5 [KO:K05428]
3596  IL13; interleukin 13 [KO:K05435]
4094  MAF; MAF bZIP transcription factor [KO:K09035]
182  JAG1; jagged canonical Notch ligand 1 [KO:K06052]
3714  JAG2; jagged canonical Notch ligand 2 [KO:K21635]
4851  NOTCH1; notch receptor 1 [KO:K02599]
4853  NOTCH2; notch receptor 2 [KO:K20994]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:19375293
  Authors
Amsen D, Spilianakis CG, Flavell RA
  Title
How are T(H)1 and T(H)2 effector cells made?
  Journal
Curr Opin Immunol 21:153-60 (2009)
DOI:10.1016/j.coi.2009.03.010
Reference
PMID:22044277
  Authors
Knosp CA, Johnston JA
  Title
Regulation of CD4+ T-cell polarization by suppressor of cytokine signalling proteins.
  Journal
Immunology 135:101-11 (2012)
DOI:10.1111/j.1365-2567.2011.03520.x
Reference
PMID:11752608
  Authors
Dong C, Flavell RA
  Title
Control of T helper cell differentiation--in search of master genes.
  Journal
Sci STKE 2000:pe1 (2000)
DOI:10.1126/stke.2000.49.pe1
Reference
PMID:11121747
  Authors
O'Garra A, Arai N
  Title
The molecular basis of T helper 1 and T helper 2 cell differentiation.
  Journal
Trends Cell Biol 10:542-50 (2000)
DOI:10.1016/S0962-8924(00)01856-0
Reference
PMID:23624818
  Authors
Hong CC, Yao S, McCann SE, Dolnick RY, Wallace PK, Gong Z, Quan L, Lee KP, Evans SS, Repasky EA, Edge SB, Ambrosone CB
  Title
Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers.
  Journal
Breast Cancer Res Treat 139:477-88 (2013)
DOI:10.1007/s10549-013-2549-3
Reference
PMID:23405903
  Authors
Kolls JK
  Title
CD4(+) T-cell subsets and host defense in the lung.
  Journal
Immunol Rev 252:156-63 (2013)
DOI:10.1111/imr.12030
Reference
PMID:20969597
  Authors
Zhu J, Paul WE
  Title
Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors.
  Journal
Immunol Rev 238:247-62 (2010)
DOI:10.1111/j.1600-065X.2010.00951.x
Reference
PMID:19151746
  Authors
Wilson CB, Rowell E, Sekimata M
  Title
Epigenetic control of T-helper-cell differentiation.
  Journal
Nat Rev Immunol 9:91-105 (2009)
DOI:10.1038/nri2487
Reference
PMID:15819694
  Authors
Callard RE, Yates AJ
  Title
Immunology and mathematics: crossing the divide.
  Journal
Immunology 115:21-33 (2005)
DOI:10.1111/j.1365-2567.2005.02142.x
Reference
PMID:24113868
  Authors
Lazarevic V, Glimcher LH, Lord GM
  Title
T-bet: a bridge between innate and adaptive immunity.
  Journal
Nat Rev Immunol 13:777-89 (2013)
DOI:10.1038/nri3536
Reference
PMID:12171942
  Authors
Weigmann B, Neurath MF
  Title
T-bet and mucosal Th1 responses in the gastrointestinal tract.
  Journal
Gut 51:301-3 (2002)
DOI:10.1136/gut.51.3.301
Reference
PMID:19362457
  Authors
Adamson AS, Collins K, Laurence A, O'Shea JJ
  Title
The Current STATus of lymphocyte signaling: new roles for old players.
  Journal
Curr Opin Immunol 21:161-6 (2009)
DOI:10.1016/j.coi.2009.03.013
Reference
PMID:20065998
  Authors
Zhu J
  Title
Transcriptional regulation of Th2 cell differentiation.
  Journal
Immunol Cell Biol 88:244-9 (2010)
DOI:10.1038/icb.2009.114
Reference
PMID:26044597
  Authors
Zhu J
  Title
T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production.
  Journal
Cytokine 75:14-24 (2015)
DOI:10.1016/j.cyto.2015.05.010
Reference
PMID:19151747
  Authors
Ho IC, Tai TS, Pai SY
  Title
GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation.
  Journal
Nat Rev Immunol 9:125-35 (2009)
DOI:10.1038/nri2476
Reference
PMID:19165228
  Authors
Amsen D, Antov A, Flavell RA
  Title
The different faces of Notch in T-helper-cell differentiation.
  Journal
Nat Rev Immunol 9:116-24 (2009)
DOI:10.1038/nri2488
Reference
PMID:23336087
  Authors
Pahan K, Mondal S
  Title
Crosstalk between Nitric Oxide and T helper cells.
  Journal
J Clin Cell Immunol 3:e109 (2012)
Reference
PMID:22566933
  Authors
Schmidt A, Oberle N, Krammer PH
  Title
Molecular mechanisms of treg-mediated T cell suppression.
  Journal
Front Immunol 3:51 (2012)
DOI:10.3389/fimmu.2012.00051
Related
pathway
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04064  NF-kappa B signaling pathway
hsa04330  Notch signaling pathway
hsa04514  Cell adhesion molecules
hsa04630  JAK-STAT signaling pathway
hsa04660  T cell receptor signaling pathway
KO pathway
ko04658   
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