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)
D04923  Mepolizumab (USAN/INN)
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)
D11867  Deuruxolitinib phosphate (USAN)
D12118  Nezulcitinib (USAN)
D12121  Acapatamab (USAN)
D12211  Ivarmacitinib (USAN)
D12212  Ivarmacitinib sulfate (USAN)
D12234  Tarlatamab (USAN)
D12368  Epcoritamab (USAN/INN)
D12721  Avitotamig (USAN)
D12724  Forimtamig (USAN/INN)
D12725  Lomedeucitinib (USAN)
D12786  Lepzacitinib (USAN)
D12941  Zasocitinib (JAN/USAN/INN)
D12985  Ompekimig (USAN)
D12993  Frevecitinib (USAN/INN)
D13040  Londamocitinib (USAN/INN)
D13041  Londamocitinib xinafoate (USAN)
D13054  Lunsekimig (USAN/INN)
D13096  Tolododekin alfa (USAN)
D13123  Envudeucitinib (USAN/INN)
D13124  Envudeucitinib hydrochloride (USAN)
D13159  Pasritamig (USAN/INN)
D13161  Peluntamig (USAN/INN)
D13251  Zocilurtatug (USAN)
D13282  Gocatamig (USAN/INN)
D13320  Ramantamig (USAN/INN)
Other DBs
GO: 0045063 0045064
Organism
Homo sapiens (human) [GN:hsa]
Gene
10683  DLL3; delta-like protein 3 isoform 1 precursor [KO:K06051]
11317  RBPJL; recombining binding protein suppressor of hairless-like protein isoform 1 [KO:K06053]
1147  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform 1 [KO:K04467] [EC:2.7.11.10]
1432  MAPK14; mitogen-activated protein kinase 14 isoform 2 [KO:K04441] [EC:2.7.11.24]
182  JAG1; protein jagged-1 precursor [KO:K06052]
2353  FOS; protein c-Fos [KO:K04379]
2625  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform 2 [KO:K17895]
27040  LAT; linker for activation of T-cells family member 1 isoform a [KO:K07362]
28514  DLL1; delta-like protein 1 precursor [KO:K06051]
30009  TBX21; T-box transcription factor TBX21 [KO:K10166]
3108  HLA-DMA; HLA class II histocompatibility antigen, DM alpha chain precursor [KO:K06752]
3109  HLA-DMB; HLA class II histocompatibility antigen, DM beta chain precursor [KO:K06752]
3111  HLA-DOA; HLA class II histocompatibility antigen, DO alpha chain precursor [KO:K06752]
3112  HLA-DOB; HLA class II histocompatibility antigen, DO beta chain precursor [KO:K06752]
3113  HLA-DPA1; HLA class II histocompatibility antigen, DP alpha 1 chain precursor [KO:K06752]
3115  HLA-DPB1; HLA class II histocompatibility antigen, DP beta 1 chain precursor [KO:K06752]
3117  HLA-DQA1; HLA class II histocompatibility antigen, DQ alpha 1 chain precursor [KO:K06752]
3118  HLA-DQA2; HLA class II histocompatibility antigen, DQ alpha 2 chain precursor [KO:K06752]
3119  HLA-DQB1; HLA class II histocompatibility antigen, DQ beta 1 chain isoform 2 precursor [KO:K06752]
3120  HLA-DQB2; HLA class II histocompatibility antigen, DQ beta 2 chain isoform 2 precursor [KO:K06752]
3122  HLA-DRA; HLA class II histocompatibility antigen, DR alpha chain precursor [KO:K06752]
3123  HLA-DRB1; major histocompatibility complex, class II, DR beta 1 precursor [KO:K06752]
3125  HLA-DRB3; major histocompatibility complex, class II, DR beta 3 precursor [KO:K06752]
3126  HLA-DRB4; major histocompatibility complex, class II, DR beta 4 precursor [KO:K06752]
3127  HLA-DRB5; major histocompatibility complex, class II, DR beta 5 precursor [KO:K06752]
3458  IFNG; interferon gamma precursor [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 isoform 1 precursor [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 isoform 2 precursor [KO:K05133]
3516  RBPJ; recombining binding protein suppressor of hairless isoform 1 [KO:K06053]
3551  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform 1 [KO:K07209] [EC:2.7.11.10]
3558  IL2; interleukin-2 precursor [KO:K05429]
3559  IL2RA; interleukin-2 receptor subunit alpha isoform 1 precursor [KO:K05068]
3560  IL2RB; interleukin-2 receptor subunit beta precursor [KO:K05069]
3561  IL2RG; cytokine receptor common subunit gamma isoform 1 precursor [KO:K05070]
3565  IL4; interleukin-4 isoform 1 precursor [KO:K05430]
3566  IL4R; interleukin-4 receptor subunit alpha isoform a precursor [KO:K05071]
3567  IL5; interleukin-5 precursor [KO:K05428]
3592  IL12A; interleukin-12 subunit alpha isoform 4 precursor [KO:K05406]
3593  IL12B; interleukin-12 subunit beta precursor [KO:K05425]
3594  IL12RB1; interleukin-12 receptor subunit beta-1 isoform 1 precursor [KO:K05063]
3595  IL12RB2; interleukin-12 receptor subunit beta-2 isoform a precursor [KO:K05064]
3596  IL13; interleukin-13 isoform 1 precursor [KO:K05435]
3714  JAG2; protein jagged-2 isoform a precursor [KO:K21635]
3716  JAK1; tyrosine-protein kinase JAK1 isoform 1 [KO:K11217] [EC:2.7.10.2]
3717  JAK2; tyrosine-protein kinase JAK2 isoform a [KO:K04447] [EC:2.7.10.2]
3718  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
3725  JUN; transcription factor Jun [KO:K04448]
3932  LCK; tyrosine-protein kinase Lck isoform a [KO:K05856] [EC:2.7.10.2]
4094  MAF; transcription factor Maf isoform b [KO:K09035]
4772  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform F [KO:K04446]
4773  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform C [KO:K17332]
4775  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform 1 [KO:K17333]
4790  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform 2 proprotein [KO:K02580]
4792  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
4793  NFKBIB; NF-kappa-B inhibitor beta isoform 1 [KO:K02581]
4794  NFKBIE; NF-kappa-B inhibitor epsilon [KO:K05872]
4851  NOTCH1; neurogenic locus notch homolog protein 1 preproprotein [KO:K02599]
4853  NOTCH2; neurogenic locus notch homolog protein 2 isoform 1 preproprotein [KO:K20994]
4854  NOTCH3; neurogenic locus notch homolog protein 3 precursor [KO:K20995]
5335  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform b [KO:K01116] [EC:3.1.4.11]
54567  DLL4; delta-like protein 4 precursor [KO:K06051]
5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha isoform 1 [KO:K04348] [EC:3.1.3.16]
5532  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform b [KO:K04348] [EC:3.1.3.16]
5533  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform 2 [KO:K04348] [EC:3.1.3.16]
5534  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
5535  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
55534  MAML3; mastermind-like protein 3 [KO:K06061]
5588  PRKCQ; protein kinase C theta type isoform 1 [KO:K18052] [EC:2.7.11.13]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 isoform 1 [KO:K04371] [EC:2.7.11.24]
5599  MAPK8; mitogen-activated protein kinase 8 isoform alpha2 [KO:K04440] [EC:2.7.11.24]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 isoform alpha2 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 isoform 1 [KO:K04440] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
5970  RELA; transcription factor p65 isoform 1 [KO:K04735]
6300  MAPK12; mitogen-activated protein kinase 12 isoform 1 [KO:K04441] [EC:2.7.11.24]
6772  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform alpha [KO:K11220]
6775  STAT4; signal transducer and activator of transcription 4 [KO:K11222]
6776  STAT5A; signal transducer and activator of transcription 5A isoform 1 [KO:K11223]
6777  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
6778  STAT6; signal transducer and activator of transcription 6 isoform 1 [KO:K11225]
7297  TYK2; non-receptor tyrosine-protein kinase TYK2 isoform 2 [KO:K11219] [EC:2.7.10.2]
7535  ZAP70; tyrosine-protein kinase ZAP-70 isoform 1 [KO:K07360] [EC:2.7.10.2]
84441  MAML2; mastermind-like protein 2 [KO:K06061]
8517  IKBKG; NF-kappa-B essential modulator isoform a [KO:K07210]
864  RUNX3; runt-related transcription factor 3 isoform 2 [KO:K09279]
915  CD3D; T-cell surface glycoprotein CD3 delta chain isoform A precursor [KO:K06450]
916  CD3E; T-cell surface glycoprotein CD3 epsilon chain precursor [KO:K06451]
917  CD3G; T-cell surface glycoprotein CD3 gamma chain precursor [KO:K06452]
919  CD247; T-cell surface glycoprotein CD3 zeta chain isoform 1 precursor [KO:K06453]
920  CD4; T-cell surface glycoprotein CD4 isoform 1 precursor [KO:K06454]
9794  MAML1; mastermind-like protein 1 [KO:K06061]
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 molecule (CAM) interaction
hsa04630  JAK-STAT signaling pathway
hsa04660  T cell receptor signaling pathway
KO pathway
ko04658   

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