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Gene Review

CD28  -  CD28 molecule

Homo sapiens

Synonyms: T-cell-specific surface glycoprotein CD28, TP44
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Disease relevance of CD28


Psychiatry related information on CD28


High impact information on CD28

  • The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells [7].
  • Recently, molecular homologs of CD28 and CTLA-4 receptors and their B7-like ligands have been identified [8].
  • ICOS is a CD28-like costimulatory receptor with a unique B7-like ligand [8].
  • We present evidence that suggests that multiple mechanisms contribute to CD28/B7-mediated T cell costimulation in disease settings that include expansion of activated pathogenic T cells, differentiation of Th1/Th2 cells, and the migration of T cells into target tissues [9].
  • This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation [10].

Chemical compound and disease context of CD28

  • In vitro binding studies have demonstrated that the via CD28-induced signal synergizes with either phorbol myristate acetate or anti-CD3 for the induction of a nuclear factor that binds CD28RE and the human immunodeficiency virus (HIV-1) NF-kB motif [11].
  • In this study we demonstrate that the HIV-1 gp41 peptide aa581-597 inhibits lymphoproliferation stimulated via the distinct T-cell-activation molecules CD3, CD2, and CD28, as well as direct stimulation mediated by phorbol ester combined with ionomycin [12].
  • IL-4 amplified proliferation to IL-1 beta, lipopolysaccharide, peptidoglycan-polysaccharide complexes, staphylococcus enterotoxin A, and antibodies to the CD3 and CD28 receptors but not to tetanus toxoid [13].
  • These studies show that signaling events initiated by tyrosine 200 of CD28 are required for efficient expression of HIV-1 transcription in activated T cells [14].
  • T cell lines expressing CD8alpha/28 chimeric receptors containing a mutation in tyrosine 173 to phenylalanine, which inhibits the recruitment of phosphatidylinositol 3-kinase (PI3K) to CD28, expressed higher levels of HIV-1 following T cell activation [15].

Biological context of CD28


Anatomical context of CD28


Associations of CD28 with chemical compounds

  • PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains [20].
  • Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway [21].
  • Treatment with rapamycin blocked IL-2 production after activation of human peripheral blood T cells with phorbol ester (PMA) and anti-CD28 (CsA-resistant pathway), whereas this drug did not have any effect on PMA plus ionomycin stimulation (CsA-sensitive pathway) [21].
  • This is explained at least in part by the long-term downregulation of I kappa B alpha following CD28 signalling as opposed to phorbol myristate acetate alone [22].
  • Nuclear run-on experiments showed that the inhibitory effects of db-cAMP and PGE2 were accomplished at transcriptional level in Con A-activated T cells, whereas changes at transcriptional and posttranscriptional level were involved in alpha CD3/alpha CD28-activated T lymphocytes [23].

Physical interactions of CD28

  • CD80 can provide a critical costimulatory signal to T cells by interacting with the T cell surface molecule CD28 [24].
  • CD80 and CD86 interact with CD28 and deliver costimulatory signals required for T cell activation [25].
  • 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 [26].
  • To dissect the molecular basis for the unusually persistent transcription of the IL-2R alpha gene, we analyzed nuclear NF-kappa B binding to a radiolabeled IL-2R alpha kappa B-specific oligonucleotide probe during the time course of CD2 + CD28 activation [27].
  • Therefore the Rac1/CDC42-coupled pathway(s) is a candidate that transduces and facilitates cross-talk between the CD28 costimulatory signal and the TCR signal [28].

Enzymatic interactions of CD28

  • We demonstrate that EMT can phosphorylate all four tyrosines of the CD28 tail, in contrast to LCK, which phosphorylates only tyrosine 173 [29].

Regulatory relationships of CD28


Other interactions of CD28

  • Selective CD28pYMNM mutations implicate phosphatidylinositol 3-kinase in CD86-CD28-mediated costimulation [33].
  • The CD28 receptor regulates the production of multiple lymphokines, including interleukin 2 (IL-2), by activation of a signal transduction pathway that is poorly understood [34].
  • 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 [35].
  • In contrast to Con A and alpha CD3/alpha CD28 activation, phorbol myristate acetate plus A23187-induced IL-4 mRNA expression was insensitive to the inhibitory effect of db-cAMP and PGE2 [23].
  • Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells [36].

Analytical, diagnostic and therapeutic context of CD28

  • In the present study, we use surface plasmon resonance to measure the affinity and kinetics of CD80 binding to CD28 and CTLA-4 [35].
  • The anti-CD28 fusion molecule showed biologic activity as an immuno-suppressant by inhibiting T-cell activation and proliferation in a mixed lymphocyte reaction [37].
  • This review will highlight recent findings regarding the CD28 family with special emphasis on effects the CD28 family has on immunopathology, the discovery of costimulatory antibodies with superagonist function, and the status of clinical trials using various strategies to augment or block T-cell costimulation [38].
  • 3H1-DC vaccination resulted in augmented CTL responses and the elevated expression of CD69, CD25, and CD28 on CD8(+) CTLs [39].
  • We tested the effects of blocking CD28-B7 T cell costimulation by using CTLA4Ig in an established transplantation model in which LBNF1 cardiac allografts are rejected in an accelerated manner (<36 h) by LEW rats presensitized with Brown-Norway skin grafts [40].


  1. Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Ott, M., Emiliani, S., Van Lint, C., Herbein, G., Lovett, J., Chirmule, N., McCloskey, T., Pahwa, S., Verdin, E. Science (1997) [Pubmed]
  2. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. Abrams, J.R., Kelley, S.L., Hayes, E., Kikuchi, T., Brown, M.J., Kang, S., Lebwohl, M.G., Guzzo, C.A., Jegasothy, B.V., Linsley, P.S., Krueger, J.G. J. Exp. Med. (2000) [Pubmed]
  3. Defective expression of p56lck in an infant with severe combined immunodeficiency. Goldman, F.D., Ballas, Z.K., Schutte, B.C., Kemp, J., Hollenback, C., Noraz, N., Taylor, N. J. Clin. Invest. (1998) [Pubmed]
  4. Endogenous CD28 expressed on myeloma cells up-regulates interleukin-8 production: implications for multiple myeloma progression. Shapiro, V.S., Mollenauer, M.N., Weiss, A. Blood (2001) [Pubmed]
  5. Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses. Tzachanis, D., Berezovskaya, A., Nadler, L.M., Boussiotis, V.A. Blood (2002) [Pubmed]
  6. Expansions of CD8+CD28- and CD8+TcRVbeta5.2+ T cells in peripheral blood of heavy alcohol drinkers. Arosa, F.A., Porto, G., Cabeda, J.M., Lacerda, R., Resende, D., Cruz, E., Cardoso, C., Fonseca, M., Simões, C., Rodrigues, P., Bravo, F., Oliveira, J.C., Alves, H., Fraga, J., Justiça, B., de Sousa, M. Alcohol. Clin. Exp. Res. (2000) [Pubmed]
  7. The B7 family revisited. Greenwald, R.J., Freeman, G.J., Sharpe, A.H. Annu. Rev. Immunol. (2005) [Pubmed]
  8. 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]
  9. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Salomon, B., Bluestone, J.A. Annu. Rev. Immunol. (2001) [Pubmed]
  10. CD28/B7 system of T cell costimulation. Lenschow, D.J., Walunas, T.L., Bluestone, J.A. Annu. Rev. Immunol. (1996) [Pubmed]
  11. Activation of interleukin-2 gene transcription via the T-cell surface molecule CD28 is mediated through an NF-kB-like response element. Verweij, C.L., Geerts, M., Aarden, L.A. J. Biol. Chem. (1991) [Pubmed]
  12. A synthetic peptide with sequence identity to the transmembrane protein GP41 of HIV-1 inhibits distinct lymphocyte activation pathways dependent on protein kinase C and intracellular calcium influx. Ruegg, C.L., Strand, M. Cell. Immunol. (1991) [Pubmed]
  13. Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity. West, G.A., Matsuura, T., Levine, A.D., Klein, J.S., Fiocchi, C. Gastroenterology (1996) [Pubmed]
  14. CD28-dependent HIV-1 transcription is associated with Vav, Rac, and NF-kappa B activation. Cook, J.A., Albacker, L., August, A., Henderson, A.J. J. Biol. Chem. (2003) [Pubmed]
  15. Recruitment of phosphatidylinositol 3-kinase to CD28 inhibits HIV transcription by a Tat-dependent mechanism. Cook, J.A., August, A., Henderson, A.J. J. Immunol. (2002) [Pubmed]
  16. The role of the CD28 receptor during T cell responses to antigen. Linsley, P.S., Ledbetter, J.A. Annu. Rev. Immunol. (1993) [Pubmed]
  17. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Hutloff, A., Dittrich, A.M., Beier, K.C., Eljaschewitsch, B., Kraft, R., Anagnostopoulos, I., Kroczek, R.A. Nature (1999) [Pubmed]
  18. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Fraser, J.D., Irving, B.A., Crabtree, G.R., Weiss, A. Science (1991) [Pubmed]
  19. CD28 and T cell antigen receptor signal transduction coordinately regulate interleukin 2 gene expression in response to superantigen stimulation. Fraser, J.D., Newton, M.E., Weiss, A. J. Exp. Med. (1992) [Pubmed]
  20. p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation. Raab, M., Cai, Y.C., Bunnell, S.C., Heyeck, S.D., Berg, L.J., Rudd, C.E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  21. Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway. Ghosh, P., Buchholz, M.A., Yano, S., Taub, D., Longo, D.L. Blood (2002) [Pubmed]
  22. Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells. Bryan, R.G., Li, Y., Lai, J.H., Van, M., Rice, N.R., Rich, R.R., Tan, T.H. Mol. Cell. Biol. (1994) [Pubmed]
  23. Interleukin-4 gene expression in activated human T lymphocytes is regulated by the cyclic adenosine monophosphate-dependent signaling pathway. Borger, P., Kauffman, H.F., Postma, D.S., Vellenga, E. Blood (1996) [Pubmed]
  24. Identification of residues in the V domain of CD80 (B7-1) implicated in functional interactions with CD28 and CTLA4. Fargeas, C.A., Truneh, A., Reddy, M., Hurle, M., Sweet, R., Sékaly, R.P. J. Exp. Med. (1995) [Pubmed]
  25. Essential role for both CD80 and CD86 costimulation, but not CD40 interactions, in allergen-induced Th2 cytokine production from asthmatic bronchial tissue: role for alphabeta, but not gammadelta, T cells. Jaffar, Z.H., Stanciu, L., Pandit, A., Lordan, J., Holgate, S.T., Roberts, K. J. Immunol. (1999) [Pubmed]
  26. 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]
  27. Activation of primary human T-lymphocytes through CD2 plus CD28 adhesion molecules induces long-term nuclear expression of NF-kappa B. Costello, R., Lipcey, C., Algarté, M., Cerdan, C., Baeuerle, P.A., Olive, D., Imbert, J. Cell Growth Differ. (1993) [Pubmed]
  28. Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. Kaga, S., Ragg, S., Rogers, K.A., Ochi, A. J. Immunol. (1998) [Pubmed]
  29. Analysis of CD28 cytoplasmic tail tyrosine residues as regulators and substrates for the protein tyrosine kinases, EMT and LCK. King, P.D., Sadra, A., Teng, J.M., Xiao-Rong, L., Han, A., Selvakumar, A., August, A., Dupont, B. J. Immunol. (1997) [Pubmed]
  30. Expression of the co-stimulatory molecule BB-1, the ligands CTLA-4 and CD28 and their mRNAs in chronic inflammatory demyelinating polyneuropathy. Murata, K., Dalakas, M.C. Brain (2000) [Pubmed]
  31. CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28. Slavik, J.M., Hutchcroft, J.E., Bierer, B.E. J. Biol. Chem. (1999) [Pubmed]
  32. Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV-1 entry. Moriuchi, M., Moriuchi, H., Turner, W., Fauci, A.S. J. Immunol. (1997) [Pubmed]
  33. Selective CD28pYMNM mutations implicate phosphatidylinositol 3-kinase in CD86-CD28-mediated costimulation. Cai, Y.C., Cefai, D., Schneider, H., Raab, M., Nabavi, N., Rudd, C.E. Immunity (1995) [Pubmed]
  34. Antibody and B7/BB1-mediated ligation of the CD28 receptor induces tyrosine phosphorylation in human T cells. Vandenberghe, P., Freeman, G.J., Nadler, L.M., Fletcher, M.C., Kamoun, M., Turka, L.A., Ledbetter, J.A., Thompson, C.B., June, C.H. J. Exp. Med. (1992) [Pubmed]
  35. 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]
  36. Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen. Cardoso, A.A., Schultze, J.L., Boussiotis, V.A., Freeman, G.J., Seamon, M.J., Laszlo, S., Billet, A., Sallan, S.E., Gribben, J.G., Nadler, L.M. Blood (1996) [Pubmed]
  37. Selective blockade of CD28 and not CTLA-4 with a single-chain Fv-alpha1-antitrypsin fusion antibody. Vanhove, B., Laflamme, G., Coulon, F., Mougin, M., Vusio, P., Haspot, F., Tiollier, J., Soulillou, J.P. Blood (2003) [Pubmed]
  38. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Riley, J.L., June, C.H. Blood (2005) [Pubmed]
  39. Dendritic cells pulsed with an anti-idiotype antibody mimicking carcinoembryonic antigen (CEA) can reverse immunological tolerance to CEA and induce antitumor immunity in CEA transgenic mice. Saha, A., Chatterjee, S.K., Foon, K.A., Primus, F.J., Sreedharan, S., Mohanty, K., Bhattacharya-Chatterjee, M. Cancer Res. (2004) [Pubmed]
  40. CD28-B7 T cell costimulatory blockade by CTLA4Ig in sensitized rat recipients: induction of transplantation tolerance in association with depressed cell-mediated and humoral immune responses. Onodera, K., Chandraker, A., Schaub, M., Stadlbauer, T.H., Korom, S., Peach, R., Linsley, P.S., Sayegh, M.H., Kupiec-Weglinski, J.W. J. Immunol. (1997) [Pubmed]
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