Costimulation by the CD28 family (Homo sapiens)

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1-344-4648, 495, 636, 371631, 3229, 3019, 2036, 3840, 417, 844, 4633-354814, 1548, 49395, 6189134210, 114321, 22, 24, 25171244-4721-2326, 2728cytosolcytosolCTLA-4:PP2APhosphorylated PD-1 bound to B7DC/B7H1GRB2phospho CD28:B7-1/B7-2PD-1ADPSHP-1/SHP-2 bound to phospho PD-1CD86 monomerPAK homodimerICOSLPP2AAntigen-bearing MHC Class II: TCR with dephosphorylated CD3 zeta chain:CD4ADPPDK1:AKTSrc family tyrosine kinasesATPTPL2PI3K alphapyrophosphatepCTLA-4:Src kinases:SHP2ATPPDK1:AKT:PIP3ADPICOSSHP-1/SHP-2:pBTLA:HVEMPhosphatidylinositol-4,5-bisphosphateBTLA-HVEM complexPP2A:CTLA4:B7-1/B7-2CD28:PI3KPD-1 ligandsFYNPIP3:PDK1:active AKTpBTLA-HVEM complexADPCD28:GadsGDPLck/CskSHP-2/SHP-1CTLA-4 homodimerTORC2 complexPAK bound to Rac1 and Cdc42PDK1:AKT:PIP3ATPATPPIP3:PDK1:active AKTCD28 homodimerATPPhosphorylated ICOSATPRAC1-GTPGTPSHP-2/SHP-1PD-1:PD-1 ligandsPhosphatidylinositol-3,4,5-trisphosphateOrthophosphateVAV1ADPPI3K alphaB- and T-lymphocyte attenuator precursorPIP3:PDK1:Phospho-AKTAntigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4PP2ATribbles homolog 3SHP2Akt:pCot:pNIKGTPCD28:B7-2Phosphatidylinositol-3,4,5-trisphosphatePhosphorylated CTLA-4 bound to kinasespVav1:PIP3:Grb2:CD28CD28:Grb2CD28:B7-1Akt:pCotLck/FynGRB2-related adapter protein 2ADPATPGRB2GDPCDC42-GTPVav1 bound to PIP3 and Grb2:CD28ATPCD80 (B7-1) homodimerCDC42-GDPB7-1 homodimer/ B7-2CD28 bound to B7 ligandsActivated Rac-1 and Cdc42HVEMC-terminal modulator proteinRAC1-GDPNikATPPAKICOS:ICOSLADPSrc family tyrosine kinasesGrb2:pBTLA:HVEMICOS:PI3KADPADP4


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.

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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
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
Activated Rac-1 and

Cdc42

ComplexREACT_20094 (Reactome)
Akt:pCot ComplexREACT_19785 (Reactome)
Akt:pCot:pNIK ComplexREACT_19496 (Reactome)
Antigen-bearing MHC

Class II: TCR with dephosphorylated CD3 zeta chain:CD4

ComplexREACT_19788 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated ITAMs:CD4

ComplexREACT_12725 (Reactome)
B- and T-lymphocyte

attenuator precursor

ProteinQ7Z6A9 (UniProt)
B7-1 homodimer/

B7-2

ComplexREACT_20199 (Reactome)
BTLA-HVEM

complex

ComplexREACT_20471 (Reactome)
C-terminal

modulator protein

ProteinQ5T1C6 (UniProt)
CD28 bound to B7

ligands

ComplexREACT_19594 (Reactome)
CD28 homodimer ComplexREACT_19916 (Reactome)
CD28:B7-1 ComplexREACT_19811 (Reactome)
CD28:B7-2 ComplexREACT_20140 (Reactome)
CD28:Gads ComplexREACT_20416 (Reactome)
CD28:Grb2 ComplexREACT_20227 (Reactome)
CD28:PI3K ComplexREACT_19529 (Reactome)
CD80 (B7-1)

homodimer

ComplexREACT_19742 (Reactome)
CD86 monomer ProteinP42081 (UniProt)
CDC42-GDP ComplexREACT_20401 (Reactome)
CDC42-GTP ComplexREACT_12889 (Reactome)
CTLA-4 homodimer ComplexREACT_19654 (Reactome)
CTLA-4:PP2A ComplexREACT_19731 (Reactome)
FYN ProteinP06241 (UniProt)
GDP Metabolite17552 (ChEBI)
GRB2 ProteinP62993-1 (UniProt)
GRB2-related

adapter protein 2

ProteinO75791 (UniProt)
GTP Metabolite15996 (ChEBI)
Grb2:pBTLA:HVEM ComplexREACT_20022 (Reactome)
HVEM ProteinQ92956 (UniProt)
ICOS ProteinQ9Y6W8-1 (UniProt)
ICOS:ICOSL ComplexREACT_20114 (Reactome)
ICOS:PI3K ComplexREACT_19686 (Reactome)
ICOSL ProteinO75144 (UniProt)
Lck/Csk ProteinREACT_20288 (Reactome)
Lck/Fyn ProteinREACT_20035 (Reactome)
Nik ProteinQ99558 (UniProt)
Orthophosphate Metabolite18367 (ChEBI)
PAK ProteinREACT_19640 (Reactome)
PAK bound to Rac1

and Cdc42

ComplexREACT_19943 (Reactome)
PAK homodimer ComplexREACT_19479 (Reactome)
PD-1 ProteinQ15116 (UniProt)
PD-1 ligands ProteinREACT_20259 (Reactome)
PD-1:PD-1 ligands ComplexREACT_20041 (Reactome)
PDK1:AKT ComplexREACT_20806 (Reactome)
PDK1:AKT:PIP3 ComplexREACT_13226 (Reactome)
PI3K alpha ComplexREACT_12697 (Reactome)
PIP3:PDK1:Phospho-

AKT

ComplexREACT_12841 (Reactome)
PIP3:PDK1:active

AKT

ComplexREACT_13230 (Reactome)
PP2A ComplexREACT_10628 (Reactome)
PP2A:CTLA4:B7-

1/B7-2

ComplexREACT_19452 (Reactome)
Phosphatidylinositol-

3,4,5-trisphosphate

Metabolite16618 (ChEBI)
Phosphatidylinositol-

4,5-bisphosphate

Metabolite18348 (ChEBI)
Phosphorylated

CTLA-4 bound to kinases

ComplexREACT_19872 (Reactome)
Phosphorylated ICOS ProteinQ9Y6W8-1 (UniProt)
Phosphorylated PD-1

bound to B7DC/B7H1

ComplexREACT_19810 (Reactome)
RAC1-GDP ComplexREACT_22018 (Reactome)
RAC1-GTP ComplexREACT_21594 (Reactome)
SHP-1/SHP-2 bound

to phospho PD-1

ComplexREACT_19972 (Reactome)
SHP-1/SHP-2:

pBTLA:HVEM

ComplexREACT_19540 (Reactome)
SHP-2/SHP-1 ProteinREACT_20250 (Reactome)
SHP2 ProteinQ06124 (UniProt)
Src family tyrosine

kinases

ProteinREACT_13328 (Reactome)
TORC2 complex ComplexREACT_13222 (Reactome)
TPL2 ProteinP41279 (UniProt)
Tribbles

homolog 3

ProteinQ96RU7 (UniProt)
VAV1 ProteinP15498 (UniProt)
Vav1 bound to PIP3

and Grb2:CD28

ComplexREACT_19524 (Reactome)
pBTLA-HVEM

complex

ComplexREACT_19709 (Reactome)
pCTLA-4:Src

kinases:SHP2

ComplexREACT_19498 (Reactome)
pVav1:PIP3:Grb2:

CD28

ComplexREACT_20129 (Reactome)
phospho CD28:B7-

1/B7-2

ComplexREACT_19582 (Reactome)
pyrophosphate Metabolite29888 (ChEBI)

Annotated Interactions

No annotated interactions

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