Overview of CTLA-4
When induced CTLA-4 is transported to an activated T cell’s surface, it inhibits positively co-stimulatory signals to activated T cells. The binding of CTLA-4 to B7 molecules presented by activated T lymphocytes creates a modification of co-stimulatory signals that are vital in the immune system.
Function of CTLA-4
When a T cell is activated by recognizing its specific antigen which is presented by an antigen presenting cell in a peripheral lymphoid organ, the T cell receives co-stimulatory signals to differentiate and proliferate into armed effector T cells. Once a T cell is activated it expresses proteins that transmit co-stimulatory signals to sustain or modify clonal expansion and differentiation. CTLA-4 is a protein that inhibits co-stimulation (Janeway et al., 2005).
T cells present several molecules to drive proliferation and differentiation, but the principal co-stimulatory molecule for activation and clonal expansion expressed by T cells are the CD28 receptors. CD28 proteins bind to B7 molecules, which are expressed by antigen presenting cells (Janeway et al., 2005).
Following activation T cells begin to induce the expression of CTLA-4, which is very similar to CD28 in sequence. CTLA-4 has a higher affinity for B7 molecules; therefore it competes with CD28 molecules and eventually out-competes CD28 to bind to B7 molecules such as; B7-1 and B7-2. CTLA-4 binds to most B7 molecules and effectively sends a negative signal to T cells, which requires the elimination of the proliferative phase (Janeway et al., 2005).
Also, subsequent to T cell activation, the lymphocyte secretes the cytokine interleukin-2 (IL-2), which drives proliferation and differentiation of the cell. Activated T cells express a high affinity for IL-2 receptors, which binds to the cytokine IL-2. However, it was discovered that when CTLA-4 is induced that it decreases IL-2 production (Alegre et al., 1998). The extra cellular domain of CTLA-4 can be fused with the antibody IgG (Freeman et al., 1998). CTLA-4Ig is a protein that is induced to block the production IL-2 and CD28/B7 co-stimulation (Alegre et al., 1998).
Experiments have determined that mice lacking CTLA-4 molecules die as a result of not having effective inhibitory signals that leads to a decrease in proliferation and differentiation in T cells, which as a consequence of deadly lymphoproliferative disorders (Ostrov et al., 2000).
Figure 1. Once CD28 is cross-linked and binded to B7 molecules, the protein receptor CTLA-4 is induced for a negative co-stimulatory response. CTLA-4 binds B7 molecules with 20 times as much affinity than CD28 molecules. (Fig. 8.12 from Janeway et al., 2005 )
Structure of CTLA-4
CTLA-4 belongs to the immunological superfamily Ig and is also known as the molecule CD152. CTLA-4 is viewed as having a strand topology that resembles the V-alpha domains. CTLA-4 molecule is able to dimerize he B7 binding site away from the dimerization interface. This action allows each CTLA-4 dimer to bind 2 divalent B7 molecules (Ostrov et al., 2000). Harper et al. (1991) and Ling et al. (1999) discovered that there are 4 exons in the CTLA-4 gene. The immunoglobulin chains are connected by disulfide bonds. The top surface of the CTLA-4 molecule is formed by the CDR regions known as CDR1, 2, and 3. The CDR regions especially CDR 3 plays a major role in the binding of the B7 molecules (Ostrov et al. 2000). Dariavach et al., (1988) stated that the CTLA-4 gene was found on the human chromosome 2q33.
Figure 2. Interactive CHIME of CTLA-4 bind with a B7 molecule. From . (webpage). The green and blue images combined make the CTLA-4 molecule, which is binded to the yellow and pink B7 molecule as a consequence of inhibitory signals to shut down the proliferative phase.
What happens if CTLA-4 is mutated?
I researched information about the mutated CTLA-4 protein but no specific information was obtained to understand what would happen if CTLA-4 was mutated. However, it is possible that if a CTLA-4 molecule is mutated it would not be able to bind to B7 molecules properly, therefore leading to autoimmunity.
Theraputic Applications of CTLA-4
Psoriasis Vulgaris - Psoriasis is a chronic, recurring skin disease. An increase dosage of CTLA-4 for this type of disorder assists in a quantitative decrease in epidermal hyperplasia, which helps bring about quantitative decline in skin-infiltrating T cells (Abrams et al., 1999).
Graves Disease - Graves Disease is an autoimmune disease where the thyroid gland over-produces some of your hormones. Allele sequence of A/G or G/G on nucleotide 49 of the CTLA-4 gene in patients have shown that more people are infected with Graves Disease (Kouki et al., 2000).
Insulin-dependent Diabetes Mellitus - Insulin-dependent Diabetes Mellitus is a medical disorder where there is usually higher blood (sugar) levels after activities. The insulin-dependent diabetes mellitus patients where seen as having a sequence polymorhphism of A\G in the first exon of the CTLA-4 gene (Marron et al., 1997).
Systemic Lupus Erythematosus - Systemic Lupus Erythematosus is a chronic disease which affects joints, muscles and other parts of the body. Barreto et al. (2004) discovered that there is an linkage between the 49A-G SNP in exon 1 of the CTLA-4 gene and Systemic Lupus Erythematosus.
Alegre, Maria-Luisa, Thompson, Craig B., Gajewski, Thomas F; 1998. Second Signals for Lymphocyte Activation: B7 Receptors. Encyclopedia of Immunology. 2nd ed. Vol. 4. San Diego: Academic Press Inc. 2147-2148. Accessed 2006 Mar 13.
Freeman, J. Gordon, Boussiotis, Vassiliki A., Gribben, John G., Sharpe, Arlene H., Nadler Lee M;1998. B7 (CD80 and CD86). Encyclopedia of Immunology. 2nd ed. Vol. 1. San Diego: Academic Press Inc. 306. Accessed 2006 Mar 13.
Alegre, Maria-Luisa, Thompson, Craig B., Gajewski, Thomas F; 1998. Second Signals for Lymphocyte Activation: Cytokine Receptors. Encyclopedia of Immunology. 2nd ed. Vol. 4. San Diego: Academic Press Inc. 2149. Accessed 2006 Mar 13.
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Ostrov, David A., Shi, Wuxian, Schwartz, Jean-Claude D., Almo Steven C., Natheneson, Stanley G. 2000. Structure of Murine CTLA-4 and Its Role in Modulating T Cell Responsiveness. JSTOR: A Journal from the Davidson Library 290 (5492): 816. <http://www.jstor.org/view/00368075/sp030043/03x5169u/0?currentResult=00368075%2bsp030043%2b03x5169u%2b0%2c1F&searchUrl=http%3A%2F%2Fwww.jstor.org%2Fsearch%2FBasicResults%3Fhp%3D25%26si%3D1%26Query%3Dstructure%2Bof%2BCTLA4 >. Accessed 2006 Mar 13.
Abrams, Judith R., Lebwohl, Mark G., Guzzo, Cynthia A., Jegasothy, Brian V., Goldfarb, Michael T., Goffe, Bernard S., Menter, Alan, Lowe, Nicholas J., Krueger, Gerald, Brown, Michael J., Weiner, Russell S., Birkhofer, Martin J., Warner, Garvin L., Berry, Karen K., Linsley, Peter S., Krueger, James G., Ochs, Hans D., Kelley, Susan L., and Kang, Sewon . 1999. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. < http://www.jci.org/cgi/content/abstract/103/9/1243> Accessed 2006 Mar 15.
Harper, Ling. 1991 and 1999. Cytotoxic T Lymphocyte-Associated 4; CTLA4. < http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=123890> Accessed 2006 Mar 16.
Marron MP., Raffel LJ., Garchon HJ., Jacob CO., Serrano-Rios M., Martinez Larrad MT., Teng WP., Park Y., Zang ZX., Goldstein DR., Tao YW., Beaurain G., Bach JF., Huang HS., Luo DF., Zeidler A., Rotter JI., Yang MC., Modilevsky T., Maclaren NK., She JX. 1997. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Maclaren+NK%22%5BAuthor%5D> Accessed 2006 Mar 16.
Dariavach. 1988. Cytotoxic T Lymphocyte-Associated 4; CTLA4. < http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=123890> Accessed 2006 Mar 16.
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