Costimulation by the CD28 family (Homo sapiens)

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10, 31, 3511, 44, 60, 645, 4633, 3917, 661613, 5046, 534, 5812, 1621, 483, 2421, 4825, 3237, 43, 57, 625623614712, 16815, 28, 384, 5834, 421849, 5944, 60, 6444, 642, 14, 20, 36, 40...37, 43, 512721, 2255266, 9, 29, 30, 45...cytosolcytosolcytosolcytosolcytosolCD274 PPP2R1A HLA class II histocompatibility antigen, DQ ICOS-1 HLA class II histocompatibility antigen, DQ beta 2 chain GDPp-MAP3K14MAP3K14p-S-AKT:PIP3p-Y180-ICOS PP2A:CTLA4:B7-1/B7-2HLA class II histocompatibility antigen, DRB1-13 beta chain unknown kinasePPP2R5E PIK3CA PDPK1TRAV19 p-Y142,Y160,Y174-VAV1 HLA class II histocompatibility antigen, DR alpha chain precursor PI3K alphaTRIB3 TRAC CD80 (B7-1)homodimerAKT3 VAV1 PIK3R2 PPP2R1A GTP LCK FYN YES1 PPP2R5A AKTLCK ATPHLA class II histocompatibility antigen, DRB1-7 beta chain PIK3R3 p-Y160,Y171-CD3G CD86 CDC42 PPP2R5E GTP ADPAKT3 GTP PAK1 PPP2R5D HLA class II histocompatibility antigen, DRB1-13 beta chain PI(3,4,5)P3 PTPN11 HLA class II histocompatibility antigen, DRB1-12 beta chain PPP2CA H2OSRC-1 PPP2CA PPP2R5B HLA class II histocompatibility antigen, DRB1-12 beta chain PIK3R1 LCK p-S474-AKT2 T-cell receptor alpha chain V region PY14 precursor B7-DC,B7-H1PIK3R3 BTLAADPHLA class II histocompatibility antigen, DP alpha chain precursor CD80 HLA class II histocompatibility antigen, DQ beta 2 chain PPP2CA PP2ACDC42 p-S473-AKT1 HLA class II histocompatibility antigen, DP alpha chain precursor p-Y165,Y182-CTLA4 FYN CD274 PI(3,4,5)P3CD80 HLA class II histocompatibility antigen, DRB1-11 beta chain Antigen-bearing MHCClass II: TCR withphosphorylatedITAMs:CD4CD86 p-Y188,Y199-CD3E GDP GRB2-1p-S472-AKT3 LCK p-Y165,Y182-CTLA4 GTPHLA class II histocompatibility antigen, DR beta 4 chain PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1p-S473-AKT1 CD28 LCK PAK1 FYN,LCKCD28:PI3KPAK2 VAV1:PIP3:CD28:GRB2PPP2R5D HLA class II histocompatibility antigen, DRB3-1 beta chain precursor SRC-1 GRB2:pBTLA:HVEMADPLCK, CSKp-Y394-LCK CD80 PAK1,2,3:CDC42:GTP,RAC1:GTPPDPK1:PIP3Antigen-bearing MHCClass II: TCR withdephosphorylatedCD3 zeta chain:CD4CD4 PPP2R5C p-Y191-CD28 HLA class II histocompatibility antigen, DQ TRBV12-3 VAV1HLA class II histocompatibility antigen, DR beta 4 chain ATPCD28 homodimerATPCDC42:GTP, RAC1:GTPAntigen AKT2 PDCD1LG2 PI(3,4,5)P3 SRC-1 PTPN6 CD28 Src family tyrosinekinases (SFKs)PI(3,4,5)P3 HLA class II histocompatibility antigen, DR-1 beta chain precursor FYNPPP2R1B PTPN11 HLA class II histocompatibility antigen, DRB1-1 beta chain AKT:PIP3:THEM4/TRIB3PiPTPN11 p-T,p-S-AKTTNFRSF14 CDC42 CD28 MAPKAP1 RAC1 ADPSHP-1/SHP-2:pBTLA:HVEMTCRA LCK HLA class II histocompatibility antigen, DQ GDP HLA class II histocompatibility antigen, DQ ICOS:ICOSLpCTLA-4:Srckinases:SHP2CD80 PPP2R1B HLA class II histocompatibility antigen, DP HLA class II histocompatibility antigen, DRB1-4 beta chain GRB2-1ATPp-BTLA-HVEM complexPIK3R1 PTPN11 HLA class II histocompatibility antigen, DRB1-15 beta chain PIK3CA PDCD1LG2 BTLA-HVEM complexAKT:PIP3PAK3 PDPK1 FYN PRR5 CSK HLA class II histocompatibility antigen, DRB3-1 beta chain precursor PTPN6 PI(4,5)P2TRBC1 PPP2R5C AKT3 p-Y191-CD28 PDCD1LG2 p-Y191-CD28 CTLA4 TRBV12-3 FYN TORC2 complexp-Y180-ICOSPI(3,4,5)P3 CSK CD4 PPP2CB PPP2R5A HLA class II histocompatibility antigen, DRB1-1 beta chain CD86 PDPK1 PPP2R5C SRC-1 TCRB PDCD1:PDCD1inhibitorsBTLA TRAC TCRB CD80 p-6Y-CD247 p-T305,S472-AKT3 ATPPAK2 CD86 ADPCD28:Grb2PTPN11PPP2R5B p-Y191-CD28 PTPN11 FYN RAC1:GTPCSK GRB2-1 ICOS-1HLA class II histocompatibility antigen, DRB1-8 beta chain PPP2R5B PIK3R3 ATPFYN LCK p-Y149,Y160-CD3D LCK PIK3R2 PAK2 PPP2R5A PAK1,2,3 dimerPDCD1 PDCD1LG2 HLA class II histocompatibility antigen, DR beta 5 chain TNFRSF14 LCK PIK3R2 LYN HLA class II histocompatibility antigen, DRB1-10 beta chain ADPAKT1 p-Y223,Y248-PDCD1 CD80 CTLA-4:PP2Ap-S400-MAP3K8CD86 p-Y226,Y257,Y282-BTLA GDPCD274 PIK3R1 ICOSLG PDCD1LCK Src family tyrosinekinases (SFKs)LYN RICTOR CTLA4 CD80 FYN CD80 HLA class II histocompatibility antigen, DQ PDCD1 inhibitorsHLA class II histocompatibility antigen, DRB1-16 beta chain PDCD1 LCK CD86 HLA class II histocompatibility antigen, DRB1-15 beta chain PPP2R1B PIK3R2 YES1 PPP2R1A GTPLYN PPP2CA ICOSLGCDC42 GRAP2 FYN AKT2 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor p-T309,S474-AKT2 p-S472-AKT3 TRAV19 p-Y160,Y171-CD3G CD28 PPP2CB PTPN6,PTPN11PPiPI3K alphaGRB2-1 HLA class II histocompatibility antigen, DR alpha chain precursor PIK3CA CD80 PPP2R5A FYN FYN ATPGTP PPP2R5D CD28:GRAP2GRAP2LCK MAP3K8ATPHLA class II histocompatibility antigen, DRB1-9 beta chain precursor PPP2R5B HLA class II histocompatibility antigen, DR-1 beta chain precursor PAK1,2,3p-Y188,Y199-CD3E MLST8 CDC42:GDPHLA class II histocompatibility antigen, DRB1-14 beta chain CD86 YES1 CD28:B7-2TCRA p-Y223,Y248-PDCD1 CD28:B7-1,B7-2PTPN6 YES1 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor CTLA-4 homodimerp-Y165,Y182-CTLA-4dimer:SFKsp-Y226,Y257,Y282-BTLA TNFRSF14RAC1:GDPPP2AADPp-Y226,Y257,Y282-BTLA PPP2R5C phosphoCD28:B7-1/B7-2TNFRSF14 RAC1 AKT1 Antigen CD86 p-Y394-LCK ADPMTOR AKT1 CD247-1 PIK3R1 LCK p-Y142,160,174-VAV1:PIP3:CD28:GRB2CD86TRBC1 PAK3 PI(3,4,5)P3 B7-1 homodimer/ B7-2THEM4 CD86 ATPFYN PI(3,4,5)P3 GRB2-1 CTLA4 PTPN6,PTPN11CD274 ICOS:PI3KPAK3 HLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DP T-cell receptor alpha chain V region PY14 precursor RAC1 HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DRB1-8 beta chain p-S-AKT:PDPK1:PIP3HLA class II histocompatibility antigen, DRB1-7 beta chain PPP2R1B ADPPIK3CA PPP2R1A CD28:B7-1PPP2CB RAC1 p-Y191-CD28 PTPN6 PPP2R5E PPP2R5E CD86 PIK3R3 CD80 TNFRSF14 PPP2CB LCK p-Y149,Y160-CD3D p-Y223,248-PDCD1:B7-DC,B7-H1AKT2 HLA class II histocompatibility antigen, DQ GRB2-1 CD80 PDCD1:B7-DC,B7-H1CD86 PAK1 HLA class II histocompatibility antigen, DRB1-11 beta chain ADPCD80 CD80 PI(3,4,5)P3 p-Y191-CD28 p-T308,S473-AKT1 CDC42:GTPp-S474-AKT2 CD86 HLA class II histocompatibility antigen, DR beta 5 chain PPP2R5D HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor LYN ATPHLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DRB1-16 beta chain 119197, 651


Description

Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation.
The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity.
The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 388841
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
115025view16:56, 25 January 2021ReactomeTeamReactome version 75
113470view11:54, 2 November 2020ReactomeTeamReactome version 74
112668view16:05, 9 October 2020ReactomeTeamReactome version 73
101585view11:45, 1 November 2018ReactomeTeamreactome version 66
101121view21:29, 31 October 2018ReactomeTeamreactome version 65
100649view20:03, 31 October 2018ReactomeTeamreactome version 64
100199view16:47, 31 October 2018ReactomeTeamreactome version 63
99750view15:14, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99314view12:46, 31 October 2018ReactomeTeamreactome version 62
93892view13:43, 16 August 2017ReactomeTeamreactome version 61
93463view11:24, 9 August 2017ReactomeTeamreactome version 61
87163view19:18, 18 July 2016MkutmonOntology Term : 'adaptive immune response pathway' added !
86558view09:20, 11 July 2016ReactomeTeamreactome version 56
83406view11:08, 18 November 2015ReactomeTeamVersion54
81606view13:08, 21 August 2015ReactomeTeamVersion53
77064view08:36, 17 July 2014ReactomeTeamFixed remaining interactions
76769view12:13, 16 July 2014ReactomeTeamFixed remaining interactions
76092view10:15, 11 June 2014ReactomeTeamRe-fixing comment source
75803view11:34, 10 June 2014ReactomeTeamReactome 48 Update
75154view14:10, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74801view08:53, 30 April 2014ReactomeTeamReactome46
42022view21:51, 4 March 2011MaintBotAutomatic update
39825view05:51, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT2 ProteinP31751 (Uniprot-TrEMBL)
AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
AKT:PIP3:THEM4/TRIB3ComplexR-HSA-199453 (Reactome)
AKT:PIP3ComplexR-HSA-2317329 (Reactome)
AKTComplexR-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
ATPMetaboliteCHEBI:30616 (ChEBI)
Antigen R-ALL-173548 (Reactome)
Antigen-bearing MHC

Class II: TCR with dephosphorylated

CD3 zeta chain:CD4		ComplexR-HSA-390339 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated

ITAMs:CD4		ComplexR-HSA-203494 (Reactome)
B7-1 homodimer/ B7-2ComplexR-HSA-388762 (Reactome)
B7-DC,B7-H1ComplexR-HSA-388774 (Reactome)
BTLA ProteinQ7Z6A9 (Uniprot-TrEMBL)
BTLA-HVEM complexComplexR-HSA-389525 (Reactome)
BTLAProteinQ7Z6A9 (Uniprot-TrEMBL)
CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
CD274 ProteinQ9NZQ7 (Uniprot-TrEMBL)
CD28 ProteinP10747 (Uniprot-TrEMBL)
CD28 homodimerComplexR-HSA-179780 (Reactome)
CD28:B7-1,B7-2ComplexR-HSA-388765 (Reactome)
CD28:B7-1ComplexR-HSA-388767 (Reactome)
CD28:B7-2ComplexR-HSA-388768 (Reactome)
CD28:GRAP2ComplexR-HSA-389384 (Reactome)
CD28:Grb2ComplexR-HSA-388786 (Reactome)
CD28:PI3KComplexR-HSA-388783 (Reactome)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CD80 (B7-1) homodimerComplexR-HSA-179787 (Reactome)
CD80 ProteinP33681 (Uniprot-TrEMBL)
CD86 ProteinP42081 (Uniprot-TrEMBL)
CD86ProteinP42081 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GDPComplexR-HSA-418830 (Reactome)
CDC42:GTP, RAC1:GTPComplexR-HSA-389778 (Reactome)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CSK ProteinP41240 (Uniprot-TrEMBL)
CTLA-4 homodimerComplexR-HSA-179766 (Reactome)
CTLA-4:PP2AComplexR-HSA-389533 (Reactome)
CTLA4 ProteinP16410 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYN,LCKComplexR-HSA-2395419 (Reactome)
FYNProteinP06241 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRAP2ProteinO75791 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:pBTLA:HVEMComplexR-HSA-389921 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HLA class II histocompatibility antigen, DP ProteinP04440 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DP alpha chain precursor ProteinP20036 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01906 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01909 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01920 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ beta 2 chain ProteinP05538 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor ProteinP01920 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR alpha chain precursor ProteinP01903 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR beta 4 chain ProteinP13762 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR beta 5 chain ProteinQ30154 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR-1 beta chain precursor ProteinP01912 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-1 beta chain ProteinP04229 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-10 beta chain ProteinQ30167 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-11 beta chain ProteinP20039 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-12 beta chain ProteinQ95IE3 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-13 beta chain ProteinQ5Y7A7 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-14 beta chain