CTLA-4

Cytotoxic T-lymphocyte-associated protein 4
Structure of murine CTLA4 (CD152)
Available structures PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB List of PDB id codes 1ah1​, 1i85​, 1i8l​
Identifiers
Symbols	CTLA4 ; CD152; CELIAC3; CTLA-4; GSE; IDDM12
External IDs	Template:OMIM5 Template:MGI HomoloGene: 3820
Gene ontology Cellular component Template:GNF GO Template:GNF GO Biological process Template:GNF GO
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) is a CD28-family receptor expressed on mainly CD4+ T cells. It binds the same ligands as CD28 (CD80 and CD86 on B cells and dendritic cells), but with higher affinity than CD28. However, in contrast to CD28 which enhances cell function when bound at the same time as the T cell receptor, CTLA4 inhbits the T cell and prevents it from functioning. Intracellular CTLA4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules (i.e. CD80 and CD 86).

The intracellular domain is similar to that of CD28, in that it has no intrinisic catalytic activity and contains one YVKM motif able to bind PI3K, PP2A and SHP-2 and one proline-rich motif able to bind SH3 containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.

Clinical significance

The comparatively higher binding affinity of CTLA4 has made it a potential therapy for autoimmune diseases. It plays a role in the initial immune response to and infection of immune cells by HIV, along with the CD-1 pathway and others. Fusion proteins of CTLA4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis. The fusion protein CTLA4-Ig is commercially available as Orencia (abatacept). A second generation form of CTLA4-Ig known as belatacept is currently being tested in trials. Both of these compounds are expected to find wide use in organ transplantation.

Further reading

• Liossis SN, Sfikakis PP, Tsokos GC (1998). "Immune cell signaling aberrations in human lupus". Immunol. Res. 18 (1): 27–39. PMID 9724847.CS1 maint: Multiple names: authors list (link)
• Chang TT, Kuchroo VK, Sharpe AH (2002). "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease". Curr. Dir. Autoimmun. 5: 113–30. PMID 11826754.CS1 maint: Multiple names: authors list (link)
• Alizadeh M, Babron MC, Birebent B; et al. (2003). "Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients". Ann. Neurol. 54 (1): 119–22. doi:10.1002/ana.10617. PMID 12838528.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Chistiakov DA, Turakulov RI (2004). "CTLA-4 and its role in autoimmune thyroid disease". J. Mol. Endocrinol. 31 (1): 21–36. PMID 12914522.
• Vaidya B, Pearce S (2004). "The emerging role of the CTLA-4 gene in autoimmune endocrinopathies". Eur. J. Endocrinol. 150 (5): 619–26. PMID 15132716.
• Brand O, Gough S, Heward J (2007). "HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity?". Expert reviews in molecular medicine. 7 (23): 1–15. doi:10.1017/S1462399405009981. PMID 16229750.CS1 maint: Multiple names: authors list (link)
• Kavvoura FK, Akamizu T, Awata T; et al. (2007). "Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis". J. Clin. Endocrinol. Metab. 92 (8): 3162–70. doi:10.1210/jc.2007-0147. PMID 17504905.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)