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
Quality Tags
Ontology Terms
Saving...
No Tags!
Bibliography
View all...
Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H.; ''Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens.''; PubMedEurope PMC
Alegre ML, Frauwirth KA, Thompson CB.; ''T-cell regulation by CD28 and CTLA-4.''; PubMedEurope PMC
Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMedEurope PMC
Ellis JH, Burden MN, Vinogradov DV, Linge C, Crowe JS.; ''Interactions of CD80 and CD86 with CD28 and CTLA4.''; PubMedEurope PMC
Murphy KM, Nelson CA, Sedý JR.; ''Balancing co-stimulation and inhibition with BTLA and HVEM.''; PubMedEurope PMC
Burgering BM, Coffer PJ.; ''Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction.''; PubMedEurope PMC
Teft WA, Chau TA, Madrenas J.; ''Structure-Function analysis of the CTLA-4 interaction with PP2A.''; PubMedEurope PMC
Watanabe R, Harada Y, Takeda K, Takahashi J, Ohnuki K, Ogawa S, Ohgai D, Kaibara N, Koiwai O, Tanabe K, Toma H, Sugamura K, Abe R.; ''Grb2 and Gads exhibit different interactions with CD28 and play distinct roles in CD28-mediated costimulation.''; PubMedEurope PMC
Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, Omura K, Yagita H, Pardoll DM, Chen L, Azuma M.; ''Differential binding properties of B7-H1 and B7-DC to programmed death-1.''; PubMedEurope PMC
Keir ME, Butte MJ, Freeman GJ, Sharpe AH.; ''PD-1 and its ligands in tolerance and immunity.''; PubMedEurope PMC
Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J.; ''Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.''; PubMedEurope PMC
Masteller EL, Chuang E, Mullen AC, Reiner SL, Thompson CB.; ''Structural analysis of CTLA-4 function in vivo.''; PubMedEurope PMC
Harada Y, Ohgai D, Watanabe R, Okano K, Koiwai O, Tanabe K, Toma H, Altman A, Abe R.; ''A single amino acid alteration in cytoplasmic domain determines IL-2 promoter activation by ligation of CD28 but not inducible costimulator (ICOS).''; PubMedEurope PMC
Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, Lim L.; ''Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family.''; PubMedEurope PMC
Miyatake S, Nakaseko C, Umemori H, Yamamoto T, Saito T.; ''Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152).''; PubMedEurope PMC
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM.; ''Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.''; PubMedEurope PMC
Michel F, Grimaud L, Tuosto L, Acuto O.; ''Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells.''; PubMedEurope PMC
Sadra A, Cinek T, Arellano JL, Shi J, Truitt KE, Imboden JB.; ''Identification of tyrosine phosphorylation sites in the CD28 cytoplasmic domain and their role in the costimulation of Jurkat T cells.''; PubMedEurope PMC
Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR.; ''Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.''; PubMedEurope PMC
Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D.; ''PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta.''; PubMedEurope PMC
Koyasu S.; ''The role of PI3K in immune cells.''; PubMedEurope PMC
Pagès F, Ragueneau M, Klasen S, Battifora M, Couez D, Sweet R, Truneh A, Ward SG, Olive D.; ''Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association.''; PubMedEurope PMC
Tybulewicz VL, Ardouin L, Prisco A, Reynolds LF.; ''Vav1: a key signal transducer downstream of the TCR.''; PubMedEurope PMC
Schneider H, Cai YC, Prasad KV, Shoelson SE, Rudd CE.; ''T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras.''; PubMedEurope PMC
Szczepanowska J.; ''Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements.''; PubMedEurope PMC
Schneider H, Rudd CE.; ''Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition.''; PubMedEurope PMC
Fife BT, Bluestone JA.; ''Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways.''; PubMedEurope PMC
Daniels RH, Bokoch GM.; ''p21-activated protein kinase: a crucial component of morphological signaling?''; PubMedEurope PMC
Teng JM, King PD, Sadra A, Liu X, Han A, Selvakumar A, August A, Dupont B.; ''Phosphorylation of each of the distal three tyrosines of the CD28 cytoplasmic tail is required for CD28-induced T cell IL-2 secretion.''; PubMedEurope PMC
Nurieva RI.; ''Regulation of immune and autoimmune responses by ICOS-B7h interaction.''; PubMedEurope PMC
Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S.; ''Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase.''; PubMedEurope PMC
Zhang B, Chernoff J, Zheng Y.; ''Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA.''; PubMedEurope PMC
Kane LP, Weiss A.; ''The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3.''; PubMedEurope PMC
Slavik JM, Hutchcroft JE, Bierer BE.; ''CD28/CTLA-4 and CD80/CD86 families: signaling and function.''; PubMedEurope PMC
Rudd CE, Schneider H.; ''Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.''; PubMedEurope PMC
Richter G, Burdach S.; ''ICOS: a new costimulatory ligand/receptor pair and its role in T-cell activion.''; PubMedEurope PMC
Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L.; ''A brain serine/threonine protein kinase activated by Cdc42 and Rac1.''; PubMedEurope PMC
Baroja ML, Vijayakrishnan L, Bettelli E, Darlington PJ, Chau TA, Ling V, Collins M, Carreno BM, Madrenas J, Kuchroo VK.; ''Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A.''; PubMedEurope PMC
Acuto O, Michel F.; ''CD28-mediated co-stimulation: a quantitative support for TCR signalling.''; PubMedEurope PMC
Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D.; ''Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav.''; PubMedEurope PMC
Carter LL, Carreno BM.; ''Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activation.''; PubMedEurope PMC
Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMedEurope PMC
Han J, Das B, Wei W, Van Aelst L, Mosteller RD, Khosravi-Far R, Westwick JK, Der CJ, Broek D.; ''Lck regulates Vav activation of members of the Rho family of GTPases.''; PubMedEurope PMC
Truneh A, Reddy M, Ryan P, Lyn SD, Eichman C, Couez D, Hurle MR, Sekaly RP, Olive D, Sweet R.; ''Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and B70 (B7.2): analysis by site directed mutagenesis.''; PubMedEurope PMC
Wittwer T, Schmitz ML.; ''NIK and Cot cooperate to trigger NF-kappaB p65 phosphorylation.''; PubMedEurope PMC
Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH.; ''PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling.''; PubMedEurope PMC
Okkenhaug K, Rottapel R.; ''Grb2 forms an inducible protein complex with CD28 through a Src homology 3 domain-proline interaction.''; PubMedEurope PMC
Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR.; ''Identification of Protor as a novel Rictor-binding component of mTOR complex-2.''; PubMedEurope PMC
Tybulewicz VL.; ''Vav-family proteins in T-cell signalling.''; PubMedEurope PMC
Hehner SP, Hofmann TG, Dienz O, Droge W, Schmitz ML.; ''Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription.''; PubMedEurope PMC
Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC.; ''Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.''; PubMedEurope PMC
Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, Murphy KM.; ''BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.''; PubMedEurope PMC
Schneider H, Rudd CE.; ''CD28 and Grb-2, relative to Gads or Grap, preferentially co-operate with Vav1 in the activation of NFAT/AP-1 transcription.''; PubMedEurope PMC
Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL, Murphy KM.; ''B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator.''; PubMedEurope PMC
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.
Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
Class II: TCR with dephosphorylated
CD3 zeta chain:CD4Class II: TCR with phosphorylated
ITAMs:CD4