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Gene Review

Ctla4  -  cytotoxic T-lymphocyte-associated protein 4

Mus musculus

Synonyms: CTLA-4, Cd152, Ctla-4, Cytotoxic T-lymphocyte protein 4, Cytotoxic T-lymphocyte-associated antigen 4, ...
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Disease relevance of Ctla4


Psychiatry related information on Ctla4

  • After construction of a fusion protein consisting of Id and CTLA-4 (Id-CTLA4), mice immunized with the fusion protein induced high titers of Id-specific antibody and T-cell proliferative responses without adjuvants and were protected from lethal tumor challenge [6].
  • These findings suggest a new approach for regulating IgE-mediated allergic immune responses by blockade of CTLA-4 during a critical period of Ag sensitization [7].

High impact information on Ctla4

  • Additionally, the negative regulatory role of CTLA-4 in autoimmune diseases and graft rejection supports a dynamic but complex process of immune regulation that is prominent in the control of self-reactivity [8].
  • Similar to animals that lack expression of either Ctla-4 or Tgf-beta, the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8- T-cell activity [9].
  • Interaction of the B7 molecule on antigen-presenting cells with its receptors CD28 and CTLA-4 on T cells provides costimulatory signals for T cell activation [10].
  • In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4 [11].
  • Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity [12].

Chemical compound and disease context of Ctla4


Biological context of Ctla4

  • Future experiments to test the identity of Idd5.1 and Idd5.2 as Ctla4 and Nramp1, respectively, can now be justified using approaches to specifically alter or mimic the candidate causative SNPs [17].
  • Utilizing the Jackson Lab backcross DNA panel map service, we mapped Inpp1 to chromosome 1, 1.06 cM proximal to Ctla4 [18].
  • Dimerization of CTLA-4 is required for the formation of high-avidity complexes with B7 ligands and for transmission of signals that attenuate T cell activation [19].
  • The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation [20].
  • Our data demonstrate that engagement of CTLA-4 leads to CD4(+) T cell production of TGF-beta, which, in part, contributes to the downregulation of T cell activation [21].

Anatomical context of Ctla4

  • The previously reported differential expression of Ctla4, which is induced at a lower level in NOD than in B6-activated T-cells, was found independent of Idd5.1 itself because Ctla4 expression was induced at a low level in T-cells from Idd5.1-congenic mice [22].
  • Expression of liCTLA-4, but not full-length CTLA-4 (flCTLA-4), was higher in memory/regulatory T cells from diabetes-resistant NOD congenic mice compared to susceptible NOD mice [1].
  • BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1 [23].
  • However, regulatory pathways initiated by the interactions of CTLA-4 with B7 counterligands expressed on antigen-presenting cells are not completely understood [24].
  • Administration of CTLA-4 Ig inhibited the recruitment of eosinophils into the lungs by 75% and suppressed IgE in the bronchoalveolar lavage fluid [25].

Associations of Ctla4 with chemical compounds

  • These data suggest that modulation of tryptophan catabolism is a means by which CTLA-4 functions in vivo and that CTLA-4 acts as a ligand for B7 receptor molecules that transduce intracellular signals [24].
  • In the present study, we administered the fusion protein CTLA-4 immunoglobulin (Ig) into the lungs before allergen provocation to determine whether CD28/CTLA-4 ligands are required for allergen-induced eosinophil accumulation and the production of Th2 cytokines [25].
  • Our findings identify a potent role for CTLA-4 in directing integrin adhesion and provide an alternate mechanism to account for aspects of CTLA-4 function in T cell immunity [26].
  • Interestingly, TCR ligation induces tyrosine phosphorylation of PP2AA and its dissociation from CTLA-4 when coligated [27].
  • The impact of FTY720 on Treg induction was further confirmed by concomitant in vivo blockade of CTLA4 or IL-10R which significantly abrogated its therapeutic activity [28].

Physical interactions of Ctla4

  • Here we demonstrate that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti-CD3 and anti-CD28 [29].
  • This mutant B7.1 binds CTLA4 but not CD28 [30].
  • A comparison of the effects of mutations on the binding of CD28 and CTLA4 reveals that CD28 and CTLA4 binds to the same site on B7 [31].
  • Because of mutations in the Fc gamma RI and C'1q binding sites of the Fc portion of the murine CTLA4/Fc fusion protein, the molecule binds to, but does not target, cells for Ab-dependent cellular cytotoxicity or complement-directed cytolysis [32].
  • Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition [33].

Regulatory relationships of Ctla4


Other interactions of Ctla4

  • We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4 [36].
  • Elimination of both B7-1 and B7-2 from the CTLA-4- deficient mouse abrogates the lymphocyte activation and disease, and does not reveal evidence for additional stimulatory CD28 ligands [38].
  • CTLA-4, through TGF-beta, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4(+) T cell activation [21].
  • However, the role of the two B7 receptors, CD28 and CTLA4 (CD152), on T cells in antitumor immune response has not been clearly elucidated [39].
  • Addition of IL-2 did not reverse, but Ab to CTLA-4 did reverse partially the inhibitory effect [40].

Analytical, diagnostic and therapeutic context of Ctla4

  • Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance [2].
  • Finally, administration of CTLA4-Ig to CD28/CTLA4(-/-) cardiac allograft recipients significantly prolongs graft survival [35].
  • Previously, we found that CTLA4Ig, which blocks the CD28/CTLA-4 (CD152) ligands CD80 and CD86, can be used to induce transplantation tolerance to vascularized allografts [41].
  • By flow cytometry, a stochastically regulated subpopulation of B7-1+ cells comprising 33% of total cells was detected in ES cell cultures, while negligible staining was found for B7-2, CTLA-4, and CD28 [42].
  • When B7-1, B7-2, or CTLA4 antibody was combined with IT delivery of alloantigen in the first recipient, all grafts were rejected within 14 days in second recipients after adoptive transfer [43].


  1. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Vijayakrishnan, L., Slavik, J.M., Illés, Z., Greenwald, R.J., Rainbow, D., Greve, B., Peterson, L.B., Hafler, D.A., Freeman, G.J., Sharpe, A.H., Wicker, L.S., Kuchroo, V.K. Immunity (2004) [Pubmed]
  2. Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist. Fife, B.T., Griffin, M.D., Abbas, A.K., Locksley, R.M., Bluestone, J.A. J. Clin. Invest. (2006) [Pubmed]
  3. Negative effect of CTLA-4 on induction of T-cell immunity in vivo to B7-1+, but not B7-2+, murine myelogenous leukemia. LaBelle, J.L., Hanke, C.A., Blazar, B.R., Truitt, R.L. Blood (2002) [Pubmed]
  4. Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. Perrin, P.J., Scott, D., Quigley, L., Albert, P.S., Feder, O., Gray, G.S., Abe, R., June, C.H., Racke, M.K. J. Immunol. (1995) [Pubmed]
  5. The amount of scurfin protein determines peripheral T cell number and responsiveness. Khattri, R., Kasprowicz, D., Cox, T., Mortrud, M., Appleby, M.W., Brunkow, M.E., Ziegler, S.F., Ramsdell, F. J. Immunol. (2001) [Pubmed]
  6. Enhanced antitumor immunity by fusion of CTLA-4 to a self tumor antigen. Huang, T.H., Wu, P.Y., Lee, C.N., Huang, H.I., Hsieh, S.L., Kung, J., Tao, M.H. Blood (2000) [Pubmed]
  7. Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft-versus-host disease by an enhanced expansion of regulatory CD8+ T cells. Sakurai, J., Ohata, J., Saito, K., Miyajima, H., Hirano, T., Kohsaka, T., Enomoto, S., Okumura, K., Azuma, M. J. Immunol. (2000) [Pubmed]
  8. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Salomon, B., Bluestone, J.A. Annu. Rev. Immunol. (2001) [Pubmed]
  9. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Brunkow, M.E., Jeffery, E.W., Hjerrild, K.A., Paeper, B., Clark, L.B., Yasayko, S.A., Wilkinson, J.E., Galas, D., Ziegler, S.F., Ramsdell, F. Nat. Genet. (2001) [Pubmed]
  10. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Chen, L., Ashe, S., Brady, W.A., Hellström, I., Hellström, K.E., Ledbetter, J.A., McGowan, P., Linsley, P.S. Cell (1992) [Pubmed]
  11. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Ueda, H., Howson, J.M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D.B., Hunter, K.M., Smith, A.N., Di Genova, G., Herr, M.H., Dahlman, I., Payne, F., Smyth, D., Lowe, C., Twells, R.C., Howlett, S., Healy, B., Nutland, S., Rance, H.E., Everett, V., Smink, L.J., Lam, A.C., Cordell, H.J., Walker, N.M., Bordin, C., Hulme, J., Motzo, C., Cucca, F., Hess, J.F., Metzker, M.L., Rogers, J., Gregory, S., Allahabadia, A., Nithiyananthan, R., Tuomilehto-Wolf, E., Tuomilehto, J., Bingley, P., Gillespie, K.M., Undlien, D.E., Rønningen, K.S., Guja, C., Ionescu-Tîrgovişte, C., Savage, D.A., Maxwell, A.P., Carson, D.J., Patterson, C.C., Franklyn, J.A., Clayton, D.G., Peterson, L.B., Wicker, L.S., Todd, J.A., Gough, S.C. Nature (2003) [Pubmed]
  12. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Schwartz, J.C., Zhang, X., Fedorov, A.A., Nathenson, S.G., Almo, S.C. Nature (2001) [Pubmed]
  13. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. Eagar, T.N., Karandikar, N.J., Bluestone, J.A., Miller, S.D. Eur. J. Immunol. (2002) [Pubmed]
  14. Effects of double blockade of CD28 and inducible-costimulator signaling on anti-glomerular basement membrane glomerulonephritis. Okano, K., Nitta, K., Ogawa, S., Horita, S., Habiro, K., Nihei, H., Abe, R. J. Lab. Clin. Med. (2004) [Pubmed]
  15. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Kwon, E.D., Foster, B.A., Hurwitz, A.A., Madias, C., Allison, J.P., Greenberg, N.M., Burg, M.B. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  16. Prostate cancer: advances in immunotherapy. Hurwitz, A.A., Yanover, P., Markowitz, M., Allison, J.P., Kwon, E.D. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. (2003) [Pubmed]
  17. Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. Wicker, L.S., Chamberlain, G., Hunter, K., Rainbow, D., Howlett, S., Tiffen, P., Clark, J., Gonzalez-Munoz, A., Cumiskey, A.M., Rosa, R.L., Howson, J.M., Smink, L.J., Kingsnorth, A., Lyons, P.A., Gregory, S., Rogers, J., Todd, J.A., Peterson, L.B. J. Immunol. (2004) [Pubmed]
  18. Identification and chromosomal mapping of the mouse inositol polyphosphate 1-phosphatase gene. Okabe, I., Nussbaum, R.L. Genomics (1995) [Pubmed]
  19. Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Ostrov, D.A., Shi, W., Schwartz, J.C., Almo, S.C., Nathenson, S.G. Science (2000) [Pubmed]
  20. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Tivol, E.A., Borriello, F., Schweitzer, A.N., Lynch, W.P., Bluestone, J.A., Sharpe, A.H. Immunity (1995) [Pubmed]
  21. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. Chen, W., Jin, W., Wahl, S.M. J. Exp. Med. (1998) [Pubmed]
  22. Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice. Lamhamedi-Cherradi, S.E., Boulard, O., Gonzalez, C., Kassis, N., Damotte, D., Eloy, L., Fluteau, G., Lévi-Strauss, M., Garchon, H.J. Diabetes (2001) [Pubmed]
  23. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Watanabe, N., Gavrieli, M., Sedy, J.R., Yang, J., Fallarino, F., Loftin, S.K., Hurchla, M.A., Zimmerman, N., Sim, J., Zang, X., Murphy, T.L., Russell, J.H., Allison, J.P., Murphy, K.M. Nat. Immunol. (2003) [Pubmed]
  24. CTLA-4-Ig regulates tryptophan catabolism in vivo. Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M.L., Bianchi, R., Fioretti, M.C., Puccetti, P. Nat. Immunol. (2002) [Pubmed]
  25. Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness. Tsuyuki, S., Tsuyuki, J., Einsle, K., Kopf, M., Coyle, A.J. J. Exp. Med. (1997) [Pubmed]
  26. CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Schneider, H., Valk, E., da Rocha Dias, S., Wei, B., Rudd, C.E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  27. Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. Baroja, M.L., Vijayakrishnan, L., Bettelli, E., Darlington, P.J., Chau, T.A., Ling, V., Collins, M., Carreno, B.M., Madrenas, J., Kuchroo, V.K. J. Immunol. (2002) [Pubmed]
  28. FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells. Daniel, C., Sartory, N., Zahn, N., Geisslinger, G., Radeke, H.H., Stein, J.M. J. Immunol. (2007) [Pubmed]
  29. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. Krummel, M.F., Allison, J.P. J. Exp. Med. (1996) [Pubmed]
  30. DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice. Chang, Y., Yap, S., Ge, X., Piganelli, J., Bertera, S., Giannokakis, N., Mathews, C., Prud'homme, G., Trucco, M. Gene Ther. (2005) [Pubmed]
  31. Mutational analysis and an alternatively spliced product of B7 defines its CD28/CTLA4-binding site on immunoglobulin C-like domain. Guo, Y., Wu, Y., Zhao, M., Kong, X.P., Liu, Y. J. Exp. Med. (1995) [Pubmed]
  32. Ex vivo coating of islet cell allografts with murine CTLA4/Fc promotes graft tolerance. Steurer, W., Nickerson, P.W., Steele, A.W., Steiger, J., Zheng, X.X., Strom, T.B. J. Immunol. (1995) [Pubmed]
  33. Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition. Schneider, H., Rudd, C.E. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  34. Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. Sugita, S., Streilein, J.W. J. Exp. Med. (2003) [Pubmed]
  35. B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4. Mandelbrot, D.A., Oosterwegel, M.A., Shimizu, K., Yamada, A., Freeman, G.J., Mitchell, R.N., Sayegh, M.H., Sharpe, A.H. J. Clin. Invest. (2001) [Pubmed]
  36. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. Krummel, M.F., Allison, J.P. J. Exp. Med. (1995) [Pubmed]
  37. Unresponsive CD4+ T lymphocytes from Leishmania chagasi-infected mice increase cytokine production and mediate parasite killing after blockade of B7-1/CTLA-4 molecular pathway. Gomes, N.A., Barreto-de-Souza, V., Wilson, M.E., DosReis, G.A. J. Infect. Dis. (1998) [Pubmed]
  38. B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Mandelbrot, D.A., McAdam, A.J., Sharpe, A.H. J. Exp. Med. (1999) [Pubmed]
  39. B7-CTLA4 interaction enhances both production of antitumor cytotoxic T lymphocytes and resistance to tumor challenge. Zheng, P., Wu, Y., Guo, Y., Lee, C., Liu, Y. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  40. Generation of antigen-specific, Foxp3-expressing CD4+ regulatory T cells by inhibition of APC proteosome function. Cong, Y., Konrad, A., Iqbal, N., Hatton, R.D., Weaver, C.T., Elson, C.O. J. Immunol. (2005) [Pubmed]
  41. The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. Judge, T.A., Wu, Z., Zheng, X.G., Sharpe, A.H., Sayegh, M.H., Turka, L.A. J. Immunol. (1999) [Pubmed]
  42. Embryonic stem cells and embryoid bodies express lymphocyte costimulatory molecules. Ling, V., Munroe, R.C., Murphy, E.A., Gray, G.S. Exp. Cell Res. (1998) [Pubmed]
  43. B7/CTLA4 pathway is essential for generating regulatory cells after intratracheal delivery of alloantigen in mice. Akiyama, Y., Shirasugi, N., Uchida, N., Matsumoto, K., Kitajima, M., Bashuda, H., Yagita, H., Okumura, K., Aramaki, O., Niimi, M. Transplantation (2002) [Pubmed]
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