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Gene Review

CTLA4  -  cytotoxic T-lymphocyte-associated protein 4

Homo sapiens

Synonyms: ALPS5, CD, CD152, CD28, CELIAC3, ...
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Disease relevance of CTLA4


Psychiatry related information on CTLA4


High impact information on CTLA4

  • Engagement of CTLA-4 (CD152) by the same B7-1 or B7-2 ligands results in attenuation of T cells responses [10].
  • The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen [11].
  • Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response [11].
  • Celiac disease (CD) is an intestinal disorder with multifactorial etiology [12].
  • These complexes may permit gluten-reactive T cells to provide help to tTG-specific B cells by a mechanism of intramolecular help, thereby explaining the occurrence of gluten-dependent tTG autoantibodies that is a characteristic feature of active CD [12].

Chemical compound and disease context of CTLA4


Biological context of CTLA4


Anatomical context of CTLA4

  • CD28 and CTLA4 are the B7 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells [21].
  • CTLA4 is expressed on CD4+ and CD8+ activated T cells, and also B cells, but CD28 and ICOS are largely restricted to T cells [1].
  • Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression [22].
  • In addition, rheumatoid synovial fluid T cells were positive by flow cytometric analysis for B7 (mean 20%, range 0 to 96%), as measured by staining with anti-B7 mAb or the CTLA4 Ig fusion protein, whereas no B7 expression was detected on peripheral blood T cells (mean 1%) [23].
  • Histologically, perivascular neutrophilic infiltrates were also dramatically decreased in the spinal cords of animals treated with CTLA4 but not in those treated with control human IgG [24].

Associations of CTLA4 with chemical compounds

  • Cells expressing CTLA4-KDEL do not up-regulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-immunoglobin (Ig) [22].
  • Neither VIEC nor AIEC express CTLA4-binding molecules and costimulation is blocked by cyclosporin A, suggesting that CD28 is not involved in EC costimulation of T cells [25].
  • Thus, the subcellular localization of CTLA-4 is controlled by a tyrosine-containing motif within its cytoplasmic domain [26].
  • However, cyclosporin A, which inhibits Ca(2+)/calcineurin signaling pathway, fully prevented the ionomycin- but not the cAMP-induced up-regulation of CD152 [27].
  • Although highly homologous to human CTLA4 (hCTLA4), the predicted protein sequence contains a leucine for methionine substitution at position 97 in the MYPPPY sequence [28].

Physical interactions of CTLA4

  • Preliminary reports have suggested that CD80 binds CTLA-4 and CD28 with affinities (Kd values approximately 12 and approximately 200 nM, respectively) that are high when compared with other molecular interactions that contribute to T cell-APC recognition [29].
  • B7.2 proteins expressed by SGEC were found to display distinctive binding properties denoted by the functional interaction with CD28 receptor and reduced binding to CTLA4 [30].
  • The CD86-V domain appears to have CTLA4 binding properties equivalent to that of intact CD86 [4].
  • CTLA-4 interacts with STAT5 and inhibits STAT5-mediated transcription [31].
  • CTLA-4 binding to PI 3-kinase provides further evidence that CTLA-4 is not an inert counterreceptor, but rather is coupled to an intracellular signaling molecule with the capacity to regulate cell growth [32].

Regulatory relationships of CTLA4


Other interactions of CTLA4


Analytical, diagnostic and therapeutic context of CTLA4


  1. Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study. Graham, D.S., Wong, A.K., McHugh, N.J., Whittaker, J.C., Vyse, T.J. Hum. Mol. Genet. (2006) [Pubmed]
  2. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Marron, M.P., Raffel, L.J., Garchon, H.J., Jacob, C.O., Serrano-Rios, M., Martinez Larrad, M.T., Teng, W.P., Park, Y., Zhang, Z.X., Goldstein, D.R., Tao, Y.W., Beaurain, G., Bach, J.F., Huang, H.S., Luo, D.F., Zeidler, A., Rotter, J.I., Yang, M.C., Modilevsky, T., Maclaren, N.K., She, J.X. Hum. Mol. Genet. (1997) [Pubmed]
  3. A CTLA4high genotype is associated with myasthenia gravis in thymoma patients. Chuang, W.Y., Ströbel, P., Gold, R., Nix, W., Schalke, B., Kiefer, R., Opitz, A., Klinker, E., Müller-Hermelink, H.K., Marx, A. Ann. Neurol. (2005) [Pubmed]
  4. Interactions of CD80 and CD86 with CD28 and CTLA4. Ellis, J.H., Burden, M.N., Vinogradov, D.V., Linge, C., Crowe, J.S. J. Immunol. (1996) [Pubmed]
  5. No evidence for an association of the CTLA4 gene with bipolar I disorder. Jun, T.Y., Lee, K.U., Pae, C.U., Kweon, Y.S., Chae, J.H., Bahk, W.M., Kim, K.S., Lew, T.Y., Han, H. Psychiatry and clinical neurosciences. (2004) [Pubmed]
  6. Neurologic presentation of celiac disease. Bushara, K.O. Gastroenterology (2005) [Pubmed]
  7. CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Hryniewicz, A., Boasso, A., Edghill-Smith, Y., Vaccari, M., Fuchs, D., Venzon, D., Nacsa, J., Betts, M.R., Tsai, W.P., Heraud, J.M., Beer, B., Blanset, D., Chougnet, C., Lowy, I., Shearer, G.M., Franchini, G. Blood (2006) [Pubmed]
  8. Celiac disease, brain atrophy, and dementia. Collin, P., Pirttilä, T., Nurmikko, T., Somer, H., Erilä, T., Keyriläinen, O. Neurology (1991) [Pubmed]
  9. Frequency and clinical pattern of celiac disease among siblings of celiac children. Bonamico, M., Mariani, P., Mazzilli, M.C., Triglione, P., Lionetti, P., Ferrante, P., Picarelli, A., Mesturino, A., Gemme, G., Imperato, C. J. Pediatr. Gastroenterol. Nutr. (1996) [Pubmed]
  10. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Carreno, B.M., Collins, M. Annu. Rev. Immunol. (2002) [Pubmed]
  11. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Chambers, C.A., Kuhns, M.S., Egen, J.G., Allison, J.P. Annu. Rev. Immunol. (2001) [Pubmed]
  12. Molecular basis of celiac disease. Sollid, L.M. Annu. Rev. Immunol. (2000) [Pubmed]
  13. Association of CTLA4 polymorphisms with sustained response to interferon and ribavirin therapy for chronic hepatitis C virus infection. Yee, L.J., Perez, K.A., Tang, J., van Leeuwen, D.J., Kaslow, R.A. J. Infect. Dis. (2003) [Pubmed]
  14. Development and application of cytotoxic T lymphocyte-associated antigen 4 as a protein scaffold for the generation of novel binding ligands. Hufton, S.E., van Neer, N., van den Beuken, T., Desmet, J., Sablon, E., Hoogenboom, H.R. FEBS Lett. (2000) [Pubmed]
  15. Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease. Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P.G., Usadel, K.H., Badenhoop, K. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  16. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Barcellos, L.F., Kamdar, B.B., Ramsay, P.P., Deloa, C., Lincoln, R.R., Caillier, S., Schmidt, S., Haines, J.L., Pericak-Vance, M.A., Oksenberg, J.R., Hauser, S.L. Lancet neurology. (2006) [Pubmed]
  17. Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity. Wu, G.S., Saftig, P., Peters, C., El-Deiry, W.S. Oncogene (1998) [Pubmed]
  18. CD28 and apoptosis. Boise, L.H., Noel, P.J., Thompson, C.B. Curr. Opin. Immunol. (1995) [Pubmed]
  19. Signatures of strong population differentiation shape extended haplotypes across the human CD28, CTLA4, and ICOS costimulatory genes. Butty, V., Roy, M., Sabeti, P., Besse, W., Benoist, C., Mathis, D. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  20. The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity. Hermann, R., Laine, A.P., Veijola, R., Vahlberg, T., Simell, S., Lähde, J., Simell, O., Knip, M., Ilonen, J. Diabetologia (2005) [Pubmed]
  21. A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells. Behar, S.M., Porcelli, S.A., Beckman, E.M., Brenner, M.B. J. Exp. Med. (1995) [Pubmed]
  22. Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression. Tan, P.H., Yates, J.B., Xue, S.A., Chan, C., Jordan, W.J., Harper, J.E., Watson, M.P., Dong, R., Ritter, M.A., Lechler, R.I., Lombardi, G., George, A.J. Blood (2005) [Pubmed]
  23. Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. Verwilghen, J., Lovis, R., De Boer, M., Linsley, P.S., Haines, G.K., Koch, A.E., Pope, R.M. J. Immunol. (1994) [Pubmed]
  24. Inhibition by CTLA4Ig of experimental allergic encephalomyelitis. Arima, T., Rehman, A., Hickey, W.F., Flye, M.W. J. Immunol. (1996) [Pubmed]
  25. Arterial and venular endothelial cell costimulation of cytokine secretion by human T cell clones. Johnson, D.R., Hauser, I.A., Voll, R.E., Emmrich, F. J. Leukoc. Biol. (1998) [Pubmed]
  26. Cytotoxic T lymphocyte-associated molecule-4, a high-avidity receptor for CD80 and CD86, contains an intracellular localization motif in its cytoplasmic tail. Leung, H.T., Bradshaw, J., Cleaveland, J.S., Linsley, P.S. J. Biol. Chem. (1995) [Pubmed]
  27. Cyclic adenosine 5'-monophosphate and calcium induce CD152 (CTLA-4) up-regulation in resting CD4+ T lymphocytes. Vendetti, S., Riccomi, A., Sacchi, A., Gatta, L., Pioli, C., De Magistris, M.T. J. Immunol. (2002) [Pubmed]
  28. Porcine CTLA4-Ig lacks a MYPPPY motif, binds inefficiently to human B7 and specifically suppresses human CD4+ T cell responses costimulated by pig but not human B7. Vaughan, A.N., Malde, P., Rogers, N.J., Jackson, I.M., Lechler, R.I., Dorling, A. J. Immunol. (2000) [Pubmed]
  29. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. van der Merwe, P.A., Bodian, D.L., Daenke, S., Linsley, P., Davis, S.J. J. Exp. Med. (1997) [Pubmed]
  30. Functional expression of a costimulatory B7.2 (CD86) protein on human salivary gland epithelial cells that interacts with the CD28 receptor, but has reduced binding to CTLA4. Kapsogeorgou, E.K., Moutsopoulos, H.M., Manoussakis, M.N. J. Immunol. (2001) [Pubmed]
  31. CTLA-4 interacts with STAT5 and inhibits STAT5-mediated transcription. Srahna, M., Van Grunsven, L.A., Remacle, J.E., Vandenberghe, P. Immunology (2006) [Pubmed]
  32. CTLA-4 binding to the lipid kinase phosphatidylinositol 3-kinase in T cells. Schneider, H., Prasad, K.V., Shoelson, S.E., Rudd, C.E. J. Exp. Med. (1995) [Pubmed]
  33. Ovine dendritic cells transduced with an adenoviral CTLA4eEGFP fusion protein construct induce hyporesponsiveness to allostimulation. Newland, A., Kireta, S., Russ, G., Krishnan, R. Immunology (2004) [Pubmed]
  34. Relationship between CTLA-4 and CD28 molecule expression on T lymphocytes and stimulating and blocking autoantibodies to the TSH-receptor in children with Graves' disease. Bossowski, A., Stasiak-Barmuta, A., Urban, M. Horm. Res. (2005) [Pubmed]
  35. ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement. Riley, J.L., Blair, P.J., Musser, J.T., Abe, R., Tezuka, K., Tsuji, T., June, C.H. J. Immunol. (2001) [Pubmed]
  36. Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter. Gibson, H.M., Hedgcock, C.J., Aufiero, B.M., Wilson, A.J., Hafner, M.S., Tsokos, G.C., Wong, H.K. J. Immunol. (2007) [Pubmed]
  37. Soluble CD86 is a costimulatory molecule for human T lymphocytes. Jeannin, P., Magistrelli, G., Aubry, J.P., Caron, G., Gauchat, J.F., Renno, T., Herbault, N., Goetsch, L., Blaecke, A., Dietrich, P.Y., Bonnefoy, J.Y., Delneste, Y. Immunity (2000) [Pubmed]
  38. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Boussiotis, V.A., Freeman, G.J., Gribben, J.G., Daley, J., Gray, G., Nadler, L.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  39. Increased salivary gland tissue expression of Fas, Fas ligand, cytotoxic T lymphocyte-associated antigen 4, and programmed cell death 1 in primary Sjögren's syndrome. Bolstad, A.I., Eiken, H.G., Rosenlund, B., Alarcón-Riquelme, M.E., Jonsson, R. Arthritis Rheum. (2003) [Pubmed]
  40. Expression and function of a CD5 cDNA in human and murine T cells. Nishimura, Y., Bierer, B.E., Jones, W.K., Jones, N.H., Strominger, J.L., Burakoff, S.J. Eur. J. Immunol. (1988) [Pubmed]
  41. CBLB variants in type 1 diabetes and their genetic interaction with CTLA4. Bergholdt, R., Taxvig, C., Eising, S., Nerup, J., Pociot, F. J. Leukoc. Biol. (2005) [Pubmed]
  42. The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus. Rau, H., Braun, J., Donner, H., Seissler, J., Siegmund, T., Usadel, K.H., Badenhoop, K. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  43. In vivo expression of the CTLA4 inhibitory receptor in malignant and reactive cells from human lymphomas. Xerri, L., Devilard, E., Hassoun, J., Olive, D., Birg, F. J. Pathol. (1997) [Pubmed]
  44. Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis. Croxford, J.L., O'Neill, J.K., Ali, R.R., Browne, K., Byrnes, A.P., Dallman, M.J., Wood, M.J., Fedlmann, M., Baker, D. Eur. J. Immunol. (1998) [Pubmed]
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