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CTLA-4




Cytotoxic T-lymphocyte-associated protein 4
Structure of murine CTLA4 (CD152)
Available structures: 1ah1, 1i85, 1i8l
Identifiers
Symbol(s) CTLA4; CD152; CELIAC3; CTLA-4; GSE; IDDM12
External IDs OMIM: 123890 MGI: 88556 Homologene: 3820
RNA expression pattern

Additional recommended knowledge

More reference expression data

Orthologs
Human Mouse
Entrez 1493 12477
Ensembl ENSG00000163599 ENSMUSG00000026011
Uniprot P16410 Q6GTR6
Refseq XM_001129541 (mRNA)
XP_001129541 (protein)
NM_009843 (mRNA)
NP_033973 (protein)
Location Chr 2: 204.44 - 204.45 Mb Chr 1: 60.85 - 60.86 Mb
Pubmed search [1] [2]

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.[1] 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.

References

  1. ^ http://arthritis-research.com/content/6/S1/86

Further reading

  • Liossis SN, Sfikakis PP, Tsokos GC (1998). "Immune cell signaling aberrations in human lupus.". Immunol. Res. 18 (1): 27-39. PMID 9724847.
  • 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.
  • 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.
  • 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.
  • 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.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "CTLA-4". A list of authors is available in Wikipedia.
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