|Cytotoxic T-lymphocyte-associated protein 4|
Structure of murine CTLA4 (CD152)
|RNA expression pattern|
CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152 (Cluster of differentiation 152), is a protein receptor that downregulates the immune system. CTLA4 is found on the surface of T cells, which lead the cellular immune attack on antigens. The T cell attack can be turned on by stimulating the CD28 receptor on the T cell. The T cell attack can be turned off by stimulating the CTLA4 receptor, which acts as an "off" switch.
Function and mechanism 
CTLA4 is a member of the immunoglobulin superfamily, which is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. CTLA4 is similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. 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.
Multiphoton microscopy studies observing T-cell motility in intact lymph nodes gave evidence for the so called ‘reverse-stop signaling model’. In this model CTLA 4 reverses the classic TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs).
The protein contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28, in that it has no intrinsic 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 
Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, primary biliary cirrhosis and other autoimmune diseases.
Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as autoimmune thyroid disease and multiple sclerosis, though this association is often weak. In Systemic Lupus Erythematosus (SLE), the splice variant sCTLA-4 is found to be aberrantly produced and found in the serum of patients with active SLE.
Agonists to reduce immune activity 
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 PD-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 was recently approved by the FDA based on favorable results from the randomized Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression) study. It was approved for renal transplantation in patients that are sensitized to EBV, or Epstein Barr Virus.
Antagonists to increase immune activity 
Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA4 (using antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011)) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer. This is the first approved immune checkpoint blockade therapy.
CTLA-4 has been shown to interact with:
- Dariavach P, Mattéi MG, Golstein P, Lefranc MP (December 1988). "Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains". Eur. J. Immunol. 18 (12): 1901–5. doi:10.1002/eji.1830181206. PMID 3220103.
- Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (November 1995). "Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4". Science 270 (5238): 985–8. doi:10.1126/science.270.5238.985. PMID 7481803.
- Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y (November 1999). "A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells". Eur. J. Immunol. 29 (11): 3596–602. doi:10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y. PMID 10556814.
- Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (September 2006). "Reversal of the TCR stop signal by CTLA-4". Science 313 (5795): 1972–5. doi:10.1126/science.1131078. PMID 16931720.
- Rudd CE, Taylor A, Schneider H (May 2009). "CD28 and CTLA-4 coreceptor expression and signal transduction". Immunol. Rev. 229 (1): 12–26. doi:10.1111/j.1600-065X.2009.00770.x. PMID 19426212.
- Arthritis Research & Therapy | Meeting Abstract | Abatacept (CTLA4Ig) treatment increases the remission rate in rheumatoid arthritis patients refractory to methotrexate treatment
- Pardoll DM (April 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nat. Rev. Cancer 12 (4): 252–64. doi:10.1038/nrc3239. PMID 22437870.
- Follows ER, McPheat JC, Minshull C, Moore NC, Pauptit RA, Rowsell S, Stacey CL, Stanway JJ, Taylor IW, Abbott WM (October 2001). "Study of the interaction of the medium chain mu 2 subunit of the clathrin-associated adapter protein complex 2 with cytotoxic T-lymphocyte antigen 4 and CD28". Biochem. J. 359 (Pt 2): 427–34. doi:10.1042/0264-6021:3590427. PMC 1222163. PMID 11583591.
- Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB (July 1997). "Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression". J. Immunol. 159 (1): 144–51. PMID 9200449.
- Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, Linsley PS (September 1995). "Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28". J. Biol. Chem. 270 (36): 21181–7. doi:10.1074/jbc.270.36.21181. PMID 7545666.
- Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ, Stahl ML, Seehra J, Somers WS, Mosyak L (March 2001). "Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses". Nature 410 (6828): 608–11. doi:10.1038/35069118. PMID 11279502.
- Baroja ML, Vijayakrishnan L, Bettelli E, Darlington PJ, Chau TA, Ling V, Collins M, Carreno BM, Madrenas J, Kuchroo VK (May 2002). "Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A". J. Immunol. 168 (10): 5070–8. PMID 11994459.
Further reading 
- Liossis SN, Sfikakis PP, Tsokos GC (1998). "Immune cell signaling aberrations in human lupus.". Immunol. Res. 18 (1): 27–39. doi:10.1007/BF02786511. PMID 9724847.
- Chang TT, Kuchroo VK, Sharpe AH (2002). Role of the B7-CD28/CTLA-4 Pathway in Autoimmune Disease. "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease.". Curr. Dir. Autoimmun. Current Directions in Autoimmunity 5: 113–30. doi:10.1159/000060550. ISBN 3-8055-7308-1. PMID 11826754.
- Alizadeh M, Babron MC, Birebent B, Matsuda F, Quelvennec E, Liblau R, Cournu-Rebeix I, Momigliano-Richiardi P, Sequeiros J, Yaouanq J, Genin E, Vasilescu A, Bougerie H, Trojano M, Martins Silva B, Maciel P, Clerget-Darpoux F, Clanet M, Edan G, Fontaine B, Semana G (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. doi:10.1677/jme.0.0310021. 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. doi:10.1530/eje.0.1500619. 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, Ban Y, Chistiakov DA, Frydecka I, Ghaderi A, Gough SC, Hiromatsu Y, Ploski R, Wang PW, Ban Y, Bednarczuk T, Chistiakova EI, Chojm M, Heward JM, Hiratani H, Juo SH, Karabon L, Katayama S, Kurihara S, Liu RT, Miyake I, Omrani GH, Pawlak E, Taniyama M, Tozaki T, Ioannidis JP (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.