cytotoxic T-lymphocyte-associated protein 4 (CD152) | Other immune checkpoint proteins | IUPHAR Guide to IMMUNOPHARMACOLOGY

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cytotoxic T-lymphocyte-associated protein 4 (CD152)

Target id: 2743

Nomenclature: cytotoxic T-lymphocyte-associated protein 4 (CD152)

Abbreviated Name: CTLA-4

Family: Other immune checkpoint proteins, CD molecules

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: ON :     cytotoxic T-lymphocyte-associated protein 4 (CD152) has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 223 2q33 CTLA4 cytotoxic T-lymphocyte associated protein 4
Mouse - 223 1 C Ctla4 cytotoxic T-lymphocyte-associated protein 4
Rat - 223 9q31 Ctla4 cytotoxic T-lymphocyte-associated protein 4
Previous and Unofficial Names
ICOS | cytotoxic T-lymphocyte-associated protein 4
Database Links
CATH/Gene3D
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Comments: T cell-expressed CTLA-4 binds the costimulatory molecules CD80 (Kd 208 nM) and CD86 (Kd 2000 nM) on antigen presenting cells [6]. These binding affiities were measured using surface plasmon resonance, using immobilised CD80 or CD86 and monomeric CTLA-4 in the mobile phase, but the endogenous interactions are modulated by receptor (CD80 and CD86) oligomerisation and ligand (CTLA-4) dimerisation [6].

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Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Affinity Units Reference
ipilimumab Hs Binding >9.0 pKd 7
pKd >9.0 (Kd <1x10-9 M) [7]
tremelimumab Hs Binding 8.9 pKd 8
pKd 8.9 (Kd 1.24x10-9 M) [8]
Description: Average Kd from associated patent, for a competition ELISA assessing binding of the antibody to CTLA4.
Clinically-Relevant Mutations and Pathophysiology
Disease:  Autoimmune lymphoproliferative syndrome, type V; ALPS5
Synonyms: Autoimmune lymphoproliferative syndrome [Disease Ontology: DOID:6688]
CTLA4 haploinsuffiency with autoimmune infiltration; CHAI [OMIM: 616100]
Disease Ontology: DOID:6688
OMIM: 616100
Disease:  Celiac disease, susceptibility to, 3; CELIAC3
Synonyms: Celiac disease [Orphanet: ORPHA555] [Disease Ontology: DOID:10608]
Gluten-sensitive enteropathy, susceptibility to, 3 [OMIM: 609755]
Disease Ontology: DOID:10608
OMIM: 609755
Orphanet: ORPHA555
Disease:  Diabetes mellitus, insulin-dependent, 12; IDDM12
Synonyms: Insulin-dependent diabetes mellitus 12 [OMIM: 601388]
type 1 diabetes mellitus [Disease Ontology: DOID:9744]
Disease Ontology: DOID:9744
OMIM: 601388
Disease:  Hashimoto thyroiditis
Synonyms: Autoimmune thyroiditis [Disease Ontology: DOID:7188]
Hashimoto struma [Orphanet: ORPHA855]
Disease Ontology: DOID:7188
OMIM: 140300
Orphanet: ORPHA855
Disease:  Systemic lupus erythematosus
Disease Ontology: DOID:9074
OMIM: 152700
Orphanet: ORPHA536
Gene Expression and Pathophysiology Comments
Verma et al. (2017) provide a review of the role of CTLA-4 mutations in immune deficiency and autoimmune diseases, and discuss how understanding the normal biology of this protein is helping to direct rational therapeutic development [13].
Patients with immune dysregulation caused by defective expression of the LRBA gene (Uniprot P50851) have a reduced level of CTLA-4 protein. Their symptoms are responsive to abatacept CTLA-4 'replacement' therapy [10]. Identification of LRBA mutations underlying common variable immunodeficiency with autoimmunity (CVID8) is reported in [3], [4] and [10]. Alangari et al. (2012) [1] and Lo et al. (2015) [10] noted decreased CTLA-4 expression in these patients.
General Comments
CTLA-4 is genetically linked to and evolutionarily related to CD28 [9].

References

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1. Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, Aljebreen A, Raddaoui E, Almomen AK, Al-Muhsen S, Geha RS et al.. (2012) LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J. Allergy Clin. Immunol., 130 (2): 481-8.e2. [PMID:22721650]

2. Bernett MJ, Chu SY, Leung I, Moore GL, Lee SH, Pong E, Chen H, Phung S, Muchhal US, Horton HM et al.. (2013) Immune suppression in cynomolgus monkeys by XPro9523: an improved CTLA4-Ig fusion with enhanced binding to CD80, CD86 and neonatal Fc receptor FcRn. MAbs, 5 (3): 384-96. [PMID:23549103]

3. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, Kumararatne D, Doffinger R, Thrasher AJ, Nejentsev S. (2012) LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J. Allergy Clin. Immunol., 130 (6): 1428-32. [PMID:22981790]

4. Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, Massaad MJ, Garcia-Lloret M, Hanna-Wakim R, Dbaibo G et al.. (2015) Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J. Allergy Clin. Immunol., 135 (1): 217-27. [PMID:25468195]

5. Douthwaite J, Moisan J, Privezentzev C, Soskic B, Sabbah S, Cohen S, Collinson A, England E, Huntington C, Kemp B et al.. (2017) A CD80-Biased CTLA4-Ig Fusion Protein with Superior In Vivo Efficacy by Simultaneous Engineering of Affinity, Selectivity, Stability, and FcRn Binding. J. Immunol., 198 (1): 528-537. [PMID:27881707]

6. Greene JL, Leytze GM, Emswiler J, Peach R, Bajorath J, Cosand W, Linsley PS. (1996) Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions. J. Biol. Chem., 271 (43): 26762-71. [PMID:8900156]

7. Halk EL, Korman AJ, Lonberg N. (2001) Human ctla-4 antibodies and their uses. Patent number: WO2001014424. Assignee: Medarex Inc. Priority date: 24/08/1999. Publication date: 01/03/2001.

8. Hanson DC, Neveu MJ, Mueller EE, Hanke JH, Gilman SC, Davis CG, Corvalan JR. (2004) Human monoclonal antibodies to CTLA-4. Patent number: US6682736 B1. Assignee: Abgenix, Inc., Pfizer Inc.. Priority date: 22/12/1998. Publication date: 27/01/2004.

9. Linsley PS, Ledbetter JA. (1993) The role of the CD28 receptor during T cell responses to antigen. Annu. Rev. Immunol., 11: 191-212. [PMID:8386518]

10. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R et al.. (2015) AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science, 349 (6246): 436-40. [PMID:26206937]

11. McCoy KD, Le Gros G. (1999) The role of CTLA-4 in the regulation of T cell immune responses. Immunol. Cell Biol., 77 (1): 1-10. [PMID:10101680]

12. Oshima S, Fujii Y, Karrer EE, Takamura F, Chapin SJ, Neighbors M, Viswanathan S, Devens BH, Higashi Y, Mizuhara H. (2016) Immunosuppressive effect of ASP2408, a novel CD86-selective variant of CTLA4-Ig, in rats and cynomolgus monkeys. Int. Immunopharmacol., 40: 310-317. [PMID:27662596]

13. Verma N, Burns SO, Walker LSK, Sansom DM. (2017) Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin. Exp. Immunol., 190 (1): 1-7. [PMID:28600865]

How to cite this page

Other immune checkpoint proteins: cytotoxic T-lymphocyte-associated protein 4 (CD152). Last modified on 26/01/2018. Accessed on 16/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2743.