Costimulation by the CD28 family (Homo sapiens)

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2, 38, 4323, 4416, 421439, 5511, 24, 31, 4526, 3721, 27, 53, 5495, 595, 575, 5722, 3312254, 4881017, 1915, 29, 32, 36, 41...2017, 197, 35474953, 54, 5811, 314, 4828, 5111, 31, 451934, 4016, 306, 13, 18cytosolcytosolcytosolcytosolcytosolCD80 PPP2R5A PDPK1:PIP3CD247-1 SRC-1 PPP2R5E RAC1:GTPHLA class II histocompatibility antigen, DR alpha chain precursor LCK HLA class II histocompatibility antigen, DR alpha chain precursor p-Y226,Y257,Y282-BTLA PI(3,4,5)P3 ATPPIK3R3 PTPN11 PP2AT-cell receptor alpha chain V region PY14 precursor VAV1 TNFRSF14 p-Y180-ICOS p-Y223,Y248-PDCD1 GRB2-1 FYN CDC42:GDPLCK PPP2R5A HLA class II histocompatibility antigen, DRB1-16 beta chain pCTLA-4:Srckinases:SHP2HLA class II histocompatibility antigen, DQ PIK3R1 PIK3R2 PTPN11 SRC-1 CD80 PTPN6 TRAV19 CDC42 MLST8 HLA class II histocompatibility antigen, DR-1 beta chain precursor p-S474-AKT2 GRB2-1p-Y142,160,174-VAV1:PIP3:CD28:GRB2p-Y191-CD28 AKT:PIP3:THEM4/TRIB3CD274 CD86 phosphoCD28:B7-1/B7-2PAK1,2,3:CDC42:GTP,RAC1:GTPLCK, CSKFYN PIK3CA p-Y149,Y160-CD3D PIK3R1 THEM4 LYN AKT3 HLA class II histocompatibility antigen, DQ GTPPPP2R5D H2OLCK LCK PPiHLA class II histocompatibility antigen, DRB1-4 beta chain PPP2R5B PDPK1 PPP2R5B PPP2R1B PPP2CB GTP PIK3R3 Antigen-bearing MHCClass II: TCR withdephosphorylatedCD3 zeta chain:CD4CD28 CD28 PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1HLA class II histocompatibility antigen, DP alpha chain precursor TNFRSF14MAPKAP1 YES1 p-S472-AKT3 CD274 CDC42 Antigen TRBV12-3 PI(4,5)P2PIK3R1 CD80 p-T305,S472-AKT3 HLA class II histocompatibility antigen, DRB1-14 beta chain p-S-AKT:PDPK1:PIP3PDCD1 CD80 (B7-1)homodimerPTPN11 HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DR beta 4 chain p-Y191-CD28 p-S473-AKT1 CD28:GRAP2TNFRSF14 PPP2CA PPP2R5A CD86 ADPLCK ATPAKT1 FYN PPP2R5C GDP PIK3CA PPP2R5C ADPPPP2R5A HLA class II histocompatibility antigen, DRB1-8 beta chain p-Y149,Y160-CD3D LYN PDCD1LG2 TCRB CD86 ICOSLG BTLAPPP2CB CD80 GTP PPP2R1A p-Y394-LCK HLA class II histocompatibility antigen, DRB1-15 beta chain GRAP2GTP p-MAP3K14PIK3CA HLA class II histocompatibility antigen, DRB1-10 beta chain TRBC1 FYNPAK3 PTPN6 PRR5 MAP3K8PDCD1LG2 FYN CD28:Grb2CD80 LCK CDC42 ATPp-Y188,Y199-CD3E HLA class II histocompatibility antigen, DRB1-9 beta chain precursor PAK2 GRB2:pBTLA:HVEMAKT2 GRAP2 PIK3R2 HLA class II histocompatibility antigen, DRB1-11 beta chain ATPHLA class II histocompatibility antigen, DRB1-11 beta chain PPP2R5C p-Y165,Y182-CTLA4 PI(3,4,5)P3 GRB2-1 PI(3,4,5)P3CD86 PTPN11 TNFRSF14 PIK3R3 PI(3,4,5)P3 p-Y226,Y257,Y282-BTLA CDC42:GTP, RAC1:GTPRICTOR RAC1:GDPCD80 PI(3,4,5)P3 ADPSrc family tyrosinekinases (SFKs)CD274 PAK3 PTPN6,PTPN11TRBV12-3 PTPN11 FYNp-S-AKT:PIP3PPP2R5D BTLA LCK, FYNTCRA T-cell receptor alpha chain V region PY14 precursor p-Y160,Y171-CD3G RAC1 YES1 ICOSLGTCRA PTPN6,PTPN11ADPCD28:PI3KPPP2R5B YES1 PPP2R1B CD86 AKT2 p-T309,S474-AKT2 PAK2 TRBC1 CSK PPP2CA YES1 PI3K alphaHLA class II histocompatibility antigen, DR-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-15 beta chain CD28 homodimerCTLA4 HLA class II histocompatibility antigen, DR beta 5 chain HLA class II histocompatibility antigen, DQ CD86 B7-1 homodimer/ B7-2ADPHLA class II histocompatibility antigen, DRB1-7 beta chain ICOS:ICOSLHLA class II histocompatibility antigen, DRB1-12 beta chain PPP2R5E HLA class II histocompatibility antigen, DRB3-1 beta chain precursor p-Y394-LCK TRIB3 ICOS-1 PAK2 TRAV19 p-S473-AKT1 HLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DRB1-8 beta chain TRAC VAV1:PIP3:CD28:GRB2PTPN11PPP2R5E CTLA4 ATPHLA class II histocompatibility antigen, DRB1-13 beta chain GTPPPP2CB PAK3 p-Y191-CD28 VAV1HLA class II histocompatibility antigen, DR beta 5 chain GTP PI(3,4,5)P3 HLA class II histocompatibility antigen, DRB1-7 beta chain FYN CD80 CSK PIK3CA CD86 FYN HLA class II histocompatibility antigen, DRB3-1 beta chain precursor PAK1,2,3LCK CD80 CD28 CD86 PiMAP3K14p-S474-AKT2 PI(3,4,5)P3 PPP2R5E CD86CD4 GRB2-1 CD80 PI3K alphaHLA class II histocompatibility antigen, DRB1-10 beta chain CD86 p-S472-AKT3 ICOS-1p-T308,S473-AKT1 PPP2R1A HLA class II histocompatibility antigen, DRB1-13 beta chain PTPN6 CD80 ATPCTLA-4:PP2APDCD1LG2 TRAC CD28:B7-2ADPCD86 AKT3 p-S400-MAP3K8LCK PPP2R5B AKTPAK1 HLA class II histocompatibility antigen, DQ GDPHLA class II histocompatibility antigen, DRB1-4 beta chain PDCD1:B7-DC,B7-H1CTLA4 CDC42 p-T,p-S-AKTBTLA-HVEM complexCTLA-4 homodimerPAK1 PI(3,4,5)P3 PPP2R1B LCK FYN p-Y223,248-PDCD1:B7-DC,B7-H1p-Y180-ICOSPPP2R5D HLA class II histocompatibility antigen, DRB1-1 beta chain HLA class II histocompatibility antigen, DR beta 4 chain B7-DC,B7-H1CD4 AKT:PIP3HLA class II histocompatibility antigen, DP PDPK1RAC1 LYN FYN HLA class II histocompatibility antigen, DQ PIK3R2 HLA class II histocompatibility antigen, DRB1-14 beta chain FYN p-BTLA-HVEM complexAKT3 CD80 GRB2-1 TCRB CSK AKT2 ATPMTOR Antigen-bearing MHCClass II: TCR withphosphorylatedITAMs:CD4CD28 FYN SRC-1 PAK1,2,3 dimerp-Y188,Y199-CD3E p-6Y-CD247-1 Antigen PPP2R1A PDCD1PIK3R1 FYN PIK3R2 AKT1 ATPSRC-1 HLA class II histocompatibility antigen, DP alpha chain precursor ATPLYN ADPICOS:PI3KPIK3R3 p-Y142,Y160,Y174-VAV1 CD274 PAK1 GDP LCK unknown kinaseCDC42:GTPp-Y160,Y171-CD3G p-Y191-CD28 SHP-1/SHP-2:pBTLA:HVEMRAC1 GDPCD28:B7-1,B7-2PPP2CB ADPRAC1 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor PTPN6 HLA class II histocompatibility antigen, DQ beta 2 chain AKT1 CD80 PPP2R5D CD28:B7-1PP2A:CTLA4:B7-1/B7-2HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor LCK ADPp-Y191-CD28 PPP2R1A PPP2R5C HLA class II histocompatibility antigen, DP ATPp-Y191-CD28 CD86 CD80 p-Y165,Y182-CTLA-4dimer:SFKsHLA class II histocompatibility antigen, DQ PPP2CA PDCD1LG2 PPP2R1B p-Y223,Y248-PDCD1 TNFRSF14 p-Y165,Y182-CTLA4 TORC2 complexPPP2CA HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor PDPK1 HLA class II histocompatibility antigen, DQ beta 2 chain p-Y226,Y257,Y282-BTLA LCK LCK GRB2-1Src family tyrosinekinases (SFKs)PP2AHLA class II histocompatibility antigen, DRB1-1 beta chain LCK ADPCD86 350, 52311


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: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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History

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CompareRevisionActionTimeUserComment
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:16761 (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:15422 (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)
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 ProteinQ9GIY3 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-15 beta chain ProteinP01911 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-16 beta chain ProteinQ29974 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-4 beta chain ProteinP13760 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-7 beta chain ProteinP13761 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-8 beta chain ProteinQ30134 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-9 beta chain precursor ProteinQ9TQE0 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB3-1 beta chain precursor ProteinP79483 (Uniprot-TrEMBL)
ICOS-1 ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
ICOS-1ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
ICOS:ICOSLComplexR-HSA-388788 (Reactome)
ICOS:PI3KComplexR-HSA-388785 (Reactome)
ICOSLG ProteinO75144 (Uniprot-TrEMBL)
ICOSLGProteinO75144 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCK, CSKComplexR-HSA-389743 (Reactome)
LCK, FYNComplexR-HSA-389329 (Reactome)
LYN ProteinP07948 (Uniprot-TrEMBL)
MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
MAP3K8ProteinP41279 (Uniprot-TrEMBL)
MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK1,2,3 dimerComplexR-HSA-399856 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPComplexR-HSA-389782 (Reactome)
PAK1,2,3ComplexR-HSA-390765 (Reactome)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PAK3 ProteinO75914 (Uniprot-TrEMBL)
PDCD1 ProteinQ15116 (Uniprot-TrEMBL)
PDCD1:B7-DC,B7-H1ComplexR-HSA-388800 (Reactome)
PDCD1LG2 ProteinQ9BQ51 (Uniprot-TrEMBL)
PDCD1ProteinQ15116 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alphaComplexR-HSA-198379 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)