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Gene Review

CD69  -  CD69 molecule

Homo sapiens

Synonyms: AIM, Activation inducer molecule, BL-AC/P26, C-type lectin domain family 2 member C, CLEC2C, ...
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Disease relevance of CD69


Psychiatry related information on CD69


High impact information on CD69

  • After transduction into T cells, the Hph-1-ctCTLA-4 fusion protein inhibited the production of interleukin (IL)-2, and downregulated CD69 and CD25 [8].
  • Antibodies against CD69, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact [9].
  • Raft targeting of activated SHP-1 in Jurkat-derived transfectants completely inhibited the expression of CD69 and transcriptional factors after TCR cross-linking [10].
  • Here, we report that PKCtheta function was selectively required in a Vav signaling pathway that mediates the TCR/CD28-induced activation of JNK and the IL-2 gene and the upregulation of CD69 expression [11].
  • MHC dimers, trimers, and tetramers stimulated T cells, as measured by upregulation of the activation markers CD69 and CD25, and by internalization of activated T cell receptor subunits [12].

Chemical compound and disease context of CD69


Biological context of CD69

  • The isolated cDNA exhibited a single open reading frame of 597 bp coding for CD69, and predicted a 199-amino acid protein of type II membrane topology, with extracellular (COOH-terminal), transmembrane, and intracellular domains [18].
  • ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-kappa B, and AP-1 transcription factors [19].
  • TCR stimulation of JCaM1/Fyn cells induced the expression of the CD69 activation marker and inhibited cell growth, but NFAT activation and the production of interleukin-2 were markedly reduced [20].
  • When T cells were stimulated with Bead-Leu4 in microgravity culture, they were able to partially express CD69, a receptor that is constitutively stored in intracellular pools and can be expressed in the absence of new gene expression [21].
  • Homology searches revealed sequence similarity with members of a supergene family of type II integral membrane proteins with a C-type lectin domain, indicating that CD69 is involved in signal transduction [22].

Anatomical context of CD69

  • The activation of T lymphocytes, both in vivo and in vitro, induces the expression of CD69 [18].
  • The CD69 clone hybridized to a 1.7-kb mRNA species, which was rapidly induced and degraded after lymphocyte stimulation, consistent with the presence of rapid degradation signals at the 3' untranslated region [18].
  • Anti-p75 IL-2R mAb substantially inhibits the early events associated with NK cell activation by IL-2, including inhibition of cytotoxic activity and induction of the CD69 early activation antigen [23].
  • These eosinophils have an increased viability and CD69 expression 18 h after segmental allergen provocation (SAP) which is not present in peripheral blood [24].
  • Transient expression of the polypeptide encoded by CD69 cDNA in COS-7 cells demonstrated that it presented properties comparable to native CD69 protein [18].

Associations of CD69 with chemical compounds


Physical interactions of CD69

  • Analysis of enhancer deletion mutants revealed that proximal AP-1, OCT-1/octamer-associated protein and nuclear factor of activated T cells (NFAT) binding regions were all necessary to allow CD69-mediated enhancement of CAT activity [30].

Enzymatic interactions of CD69

  • CD69 is a phosphorylated disulfide-linked homodimer that appears on the surface of human T, B cells and thymocytes in the early steps of activation; its molecular mass is 28 to 34 kDa under reducing conditions [31].

Regulatory relationships of CD69

  • When the two mAbs were used in combination, anti-CD28 potently synergized with anti-CD3 in inducing the expression of CD69 activation marker and stimulating the proliferation of CD4+ T cells [32].
  • Finally, we found that the IL-2-induced expression of CD69 was inhibited by activation of cAMP-dependent protein kinase and by inhibition of the Src-family of the tyrosine protein kinase, but not by inhibition of protein kinase C or by activation of the CD45 associated tyrosine phosphatase [33].
  • Exogenous IL-15 resulted in further enhancement of anti-CD3-induced CD69 expression to a greater extent than that achieved with IL-2 [34].
  • In contrast, the phorbol esters, PdBu or PMA had little effect on CXCR6 expression (23% reduction) but induced CD69 expression and caused a profound down-regulation (92%) of CCR5 expression [35].
  • CONCLUSION: The activation antigen CD69 is significantly expressed on PB and SF neutrophils from RA patients [36].

Other interactions of CD69

  • Although the two compounds had distinctive effects on CD69 induction, they both suppressed T cell proliferation induced by anti-CD3 mAb, in a manner reversible by exogenous IL-2, suggesting that PD98059, like FK506, affects the production of, rather than the responsiveness to growth-promoting cytokines [37].
  • This autoantibody may modulate the function of CD69- and LRP2-expressing cells [1].
  • Cross-linking of CD53 with the use of the mAb MEM-53 and a polyclonal sheep anti-mouse Ig promoted activation of resting B cells into the G1 phase of the cell cycle as judged by increased expression of the early activation Ag CD69, increases in cellular volume, RNA synthesis, and c-myc protein levels, and enhanced binding of 7-aminoactinomycin D [38].
  • METHODS: The percentage expression and mean fluorescence intensity of CR2 (and three additional markers: CD19, CD69, and a standard antigen designation: HLA-DR) was measured on CD20+ B-cells using a two-color flow cytometric assay [39].
  • OBJECTIVE: It has been well established that CD69, CD44, and CD54 represent "activation markers" for cytokine-mediated eosinophil activation [40].

Analytical, diagnostic and therapeutic context of CD69


  1. Anti-CD69 autoantibodies cross-react with low density lipoprotein receptor-related protein 2 in systemic autoimmune diseases. Yu, X., Matsui, T., Otsuka, M., Sekine, T., Yamamoto, K., Nishioka, K., Kato, T. J. Immunol. (2001) [Pubmed]
  2. Activation of CD8 T cells normalizes and correlates with the level of infectious provirus in tonsils during highly active antiretroviral therapy in early HIV-1 infection. Dyrhol-Riise, A.M., Voltersvik, P., Olofsson, J., Asjö, B. AIDS (1999) [Pubmed]
  3. Increased CD69 and human leukocyte antigen-DR expression on T lymphocytes in insulin-dependent diabetes mellitus of long standing. Gessl, A., Waldhäusl, W. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  4. Comparative analysis of alpha beta and gamma delta T cell activation by Mycobacterium tuberculosis and isopentenyl pyrophosphate. Wesch, D., Marx, S., Kabelitz, D. Eur. J. Immunol. (1997) [Pubmed]
  5. CD69 expression correlates with expression of other markers of Th1 T cell differentiation in peripheral T cell lymphomas. Dorfman, D.M., Shahsafaei, A. Hum. Pathol. (2002) [Pubmed]
  6. The bacterial superantigen Staphylococcal enterotoxin B stimulates lymphocyte locomotor capacity during culture in vitro. Newman, I., Wilkinson, P.C. Immunology (1996) [Pubmed]
  7. Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia. Kusdra, L., McGuire, D., Pulliam, L. AIDS (2002) [Pubmed]
  8. Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation. Choi, J.M., Ahn, M.H., Chae, W.J., Jung, Y.G., Park, J.C., Song, H.M., Kim, Y.E., Shin, J.A., Park, C.S., Park, J.W., Park, T.K., Lee, J.H., Seo, B.F., Kim, K.D., Kim, E.S., Lee, D.H., Lee, S.K., Lee, S.K. Nat. Med. (2006) [Pubmed]
  9. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. McInnes, I.B., Leung, B.P., Sturrock, R.D., Field, M., Liew, F.Y. Nat. Med. (1997) [Pubmed]
  10. Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts. Kosugi, A., Sakakura, J., Yasuda, K., Ogata, M., Hamaoka, T. Immunity (2001) [Pubmed]
  11. A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation. Villalba, M., Coudronniere, N., Deckert, M., Teixeiro, E., Mas, P., Altman, A. Immunity (2000) [Pubmed]
  12. The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers. Cochran, J.R., Cameron, T.O., Stern, L.J. Immunity (2000) [Pubmed]
  13. Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery. Sharma, M., Ganguly, N.K., Chaturvedi, G., Thingnam, S.K., Majumdar, S., Suri, R.K. Mol. Cell. Biochem. (2003) [Pubmed]
  14. Reciprocal activating interaction between natural killer cells and dendritic cells. Gerosa, F., Baldani-Guerra, B., Nisii, C., Marchesini, V., Carra, G., Trinchieri, G. J. Exp. Med. (2002) [Pubmed]
  15. Methimazole therapy in Graves' disease influences the abnormal expression of CD69 (early activation antigen) on T cells. Corrales, J.J., López, A., Ciudad, J., Mories, M.T., Miralles, J.M., Orfao, A. J. Endocrinol. (1997) [Pubmed]
  16. CD69 expression on peripheral CD4+ T cells parallels disease activity and is reduced by mycophenolate mofetil therapy in uveitis. Kilmartin, D.J., Fletcher, Z.J., Almeida, J.A., Liversidge, J., Forrester, J.V., Dick, A.D. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  17. Expression of CD69 after in vitro stimulation: a rapid method for quantitating impaired lymphocyte responses in HIV-infected individuals. Krowka, J.F., Cuevas, B., Maron, D.C., Steimer, K.S., Ascher, M.S., Sheppard, H.W. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. (1996) [Pubmed]
  18. Molecular cloning, expression, and chromosomal localization of the human earliest lymphocyte activation antigen AIM/CD69, a new member of the C-type animal lectin superfamily of signal-transmitting receptors. López-Cabrera, M., Santis, A.G., Fernández-Ruiz, E., Blacher, R., Esch, F., Sánchez-Mateos, P., Sánchez-Madrid, F. J. Exp. Med. (1993) [Pubmed]
  19. Modulation of T-cell receptor signal transduction by herpesvirus signaling adaptor protein. Lee, S.H., Chung, Y.H., Cho, N.H., Gwack, Y., Feng, P., Jung, J.U. Mol. Cell. Biol. (2004) [Pubmed]
  20. Differential T-cell antigen receptor signaling mediated by the Src family kinases Lck and Fyn. Denny, M.F., Patai, B., Straus, D.B. Mol. Cell. Biol. (2000) [Pubmed]
  21. T cell activation responses are differentially regulated during clinorotation and in spaceflight. Hashemi, B.B., Penkala, J.E., Vens, C., Huls, H., Cubbage, M., Sams, C.F. FASEB J. (1999) [Pubmed]
  22. Expression cloning of the early activation antigen CD69, a type II integral membrane protein with a C-type lectin domain. Hamann, J., Fiebig, H., Strauss, M. J. Immunol. (1993) [Pubmed]
  23. Activation of natural killer cells via the p75 interleukin 2 receptor. Phillips, J.H., Takeshita, T., Sugamura, K., Lanier, L.L. J. Exp. Med. (1989) [Pubmed]
  24. The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma. Nassenstein, C., Braun, A., Erpenbeck, V.J., Lommatzsch, M., Schmidt, S., Krug, N., Luttmann, W., Renz, H., Virchow, J.C. J. Exp. Med. (2003) [Pubmed]
  25. Zap-70-independent Ca(2+) mobilization and Erk activation in Jurkat T cells in response to T-cell antigen receptor ligation. Shan, X., Balakir, R., Criado, G., Wood, J.S., Seminario, M.C., Madrenas, J., Wange, R.L. Mol. Cell. Biol. (2001) [Pubmed]
  26. Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T lymphocytes. Drach, J., Gsur, A., Hamilton, G., Zhao, S., Angerler, J., Fiegl, M., Zojer, N., Raderer, M., Haberl, I., Andreeff, M., Huber, H. Blood (1996) [Pubmed]
  27. T cell activation via Leu-23 (CD69). Testi, R., Phillips, J.H., Lanier, L.L. J. Immunol. (1989) [Pubmed]
  28. Undetectable CD40 ligand expression on T cells and low B cell responses to CD40 binding agonists in human newborns. Durandy, A., De Saint Basile, G., Lisowska-Grospierre, B., Gauchat, J.F., Forveille, M., Kroczek, R.A., Bonnefoy, J.Y., Fischer, A. J. Immunol. (1995) [Pubmed]
  29. Phosphorylation of the LFA-1 Integrin beta2-Chain on Thr-758 Leads to Adhesion, Rac-1/Cdc42 Activation, and Stimulation of CD69 Expression in Human T Cells. Nurmi, S.M., Autero, M., Raunio, A.K., Gahmberg, C.G., Fagerholm, S.C. J. Biol. Chem. (2007) [Pubmed]
  30. Transcriptional regulation of interleukin-2 gene expression by CD69-generated signals. D'Ambrosio, D., Trotta, R., Vacca, A., Frati, L., Santoni, A., Gulino, A., Testi, R. Eur. J. Immunol. (1993) [Pubmed]
  31. CD69 in resting and activated T lymphocytes. Its association with a GTP binding protein and biochemical requirements for its expression. Risso, A., Smilovich, D., Capra, M.C., Baldissarro, I., Yan, G., Bargellesi, A., Cosulich, M.E. J. Immunol. (1991) [Pubmed]
  32. Engagement of CD28 modulates CXC chemokine receptor 4 surface expression in both resting and CD3-stimulated CD4+ T cells. Secchiero, P., Zella, D., Curreli, S., Mirandola, P., Capitani, S., Gallo, R.C., Zauli, G. J. Immunol. (2000) [Pubmed]
  33. Selective activation of resting human gamma delta T lymphocytes by interleukin-2. Kjeldsen-Kragh, J., Quayle, A.J., Skålhegg, B.S., Sioud, M., Førre, O. Eur. J. Immunol. (1993) [Pubmed]
  34. Effect of interleukin 15 and interleukin 2 on anti-CD3-induced T-cell activation and apoptosis in children with common variable immunodeficiency. Lin, S.J., Chao, H.C., Chang, K.W., Yan, D.C. Ann. Allergy Asthma Immunol. (2003) [Pubmed]
  35. Down-regulation of cell surface CXCR6 expression during T cell activation is predominantly mediated by calcineurin. Koprak, S., Matheravidathu, S., Springer, M., Gould, S., Dumont, F.J. Cell. Immunol. (2003) [Pubmed]
  36. CD69 expression on neutrophils from patients with rheumatoid arthritis. Atzeni, F., Del Papa, N., Sarzi-Puttini, P., Bertolazzi, F., Minonzio, F., Capsoni, F. Clinical and experimental rheumatology. (2004) [Pubmed]
  37. Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. Dumont, F.J., Staruch, M.J., Fischer, P., DaSilva, C., Camacho, R. J. Immunol. (1998) [Pubmed]
  38. Cross-linking of CD53 promotes activation of resting human B lymphocytes. Rasmussen, A.M., Blomhoff, H.K., Stokke, T., Horejsi, V., Smeland, E.B. J. Immunol. (1994) [Pubmed]
  39. In vivo decrease in the expression of complement receptor 2 on B-cells in HIV infection. Scott, M.E., Landay, A.L., Lint, T.F., Spear, G.T. AIDS (1993) [Pubmed]
  40. Activation markers of human basophils: CD69 expression is strongly and preferentially induced by IL-3. Yoshimura, C., Yamaguchi, M., Iikura, M., Izumi, S., Kudo, K., Nagase, H., Ishii, A., Walls, A.F., Ra, C., Iwata, T., Igarashi, T., Yamamoto, K., Hirai, K. J. Allergy Clin. Immunol. (2002) [Pubmed]
  41. Transcriptional regulation of the gene encoding the human C-type lectin leukocyte receptor AIM/CD69 and functional characterization of its tumor necrosis factor-alpha-responsive elements. López-Cabrera, M., Muñoz, E., Blázquez, M.V., Ursa, M.A., Santis, A.G., Sánchez-Madrid, F. J. Biol. Chem. (1995) [Pubmed]
  42. Peripheral blood mononuclear cell activation induced by Leptospira interrogans glycolipoprotein. Diament, D., Brunialti, M.K., Romero, E.C., Kallas, E.G., Salomao, R. Infect. Immun. (2002) [Pubmed]
  43. CD69 expression on peripheral CD8 T cells correlates with acute rejection in renal transplant recipients. Posselt, A.M., Vincenti, F., Bedolli, M., Lantz, M., Roberts, J.P., Hirose, R. Transplantation (2003) [Pubmed]
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