Alternative titles; symbols
HGNC Approved Gene Symbol: CD69
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:9,752,486-9,760,901 (from NCBI)
The activation of T lymphocytes, both in vivo and in vitro, induces expression of CD69. This molecule, which appears to be the earliest inducible cell surface glycoprotein acquired during lymphoid activation, is involved in lymphocyte proliferation and functions as a signal-transmitting receptor in lymphocytes, natural killer (NK) cells, and platelets (Cambiaggi et al., 1992).
Lopez-Cabrera et al. (1993) identified a cDNA for CD69 with an open reading frame predicting a 199-amino acid protein of type II membrane topology. The CD69 clone hybridized to a 1.7-kb mRNA species that was rapidly induced and degraded after lymphocyte stimulation, consistent with the presence of rapid degradation signals at the 3-prime untranslated region. Protein sequence homology search demonstrated that CD69 is a member of the same superfamily of type II transmembrane receptors as natural killer cell lectin (NKG2; 161555), which also maps to chromosome 12.
Shiow et al. (2006) demonstrated that treatment with the interferon alpha/beta (IFN-alpha/beta; 147660, 147640) inducer polyinosine polycytidylic acid inhibited egress of lymphocytes from lymphoid organs by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69-null cells were poorly retained in lymphoid tissues after treatment with polyinosine polycytidylic acid or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1; 601974), and IFN-alpha/beta inhibited lymphocyte responsiveness to S1P1. By contrast, CD69-null cells retained S1P1 function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, crosslinking led to co-crosslinking and activation of a CD69/CD3-eta chimera. CD69 coimmunoprecipitated with S1P1 but not the related receptor S1P3 (601965). Shiow et al. (2006) concluded that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.
Cambiaggi et al. (1992) produced and characterized interspecies somatic cell hybrids between human activated mature T cells and mouse BW5147 thymoma cells. A preferential segregation of human chromosomes was observed in the hybrids. They found in clones a coexpression of CD4 (186940) and CD69 antigens. Molecular and karyotypic studies of the hybrids demonstrated that the locus encoding CD69 maps to human chromosome 12, as does that for CD4. Although the expression of CD69 antigen is an early event after T-lymphocyte activation and rapidly declines in the absence of exogenous stimuli, in the hybrids they developed the expression was constitutive, similar to what is found in early thymocyte precursors and mature thymocytes. The finding suggested a dominant influence of the thymus-derived mouse tumor cell genome in controlling the constitutive expression of CD69.
By somatic cell hybrid DNA analysis and fluorescence in situ hybridization, Lopez-Cabrera et al. (1993) assigned the CD69 gene to 12p13-p12.
Sancho et al. (2003) analyzed a model of collagen-induced arthritis in wildtype and Cd69-deficient mice and found that Cd69 -/- mice showed a higher incidence and severity of arthritis, with exacerbated T- and B-cell immune responses to type II collagen. Levels of transforming growth factor-beta-1 (TGFB1; 190180) and TGFB2 (190220), which act as protective agents in collagen-induced arthritis, were reduced in Cd69-null mice inflammatory foci, correlating with an increase in proinflammatory cytokines. Local injection of blocking anti-TGF antibodies increased arthritis severity and proinflammatory cytokine mRNA levels in Cd69 wildtype but not null mice. Sancho et al. (2003) concluded that CD69 is a negative modulator of autoimmune reactivity and inflammation through the synthesis of TGFB1, a cytokine that in turn downregulates the production of various proinflammatory mediators.
Esplugues et al. (2003) observed greatly reduced growth of MHC class I-deficient tumors in Cd69 -/- mice compared with wildtype mice. The enhanced antitumor response was associated with increased local accumulation of T and NK lymphocytes and proinflammatory cytokines and decreased Tgfb production. Anti-NK cell antibody treatment restored the ability of tumors to grow in Cd69 -/- mice. An increased impairment of tumor growth occurred in mice deficient in both Cd69 and Rag2 (179616). Esplugues et al. (2003) concluded that CD69 is a negative regulator of antitumor responses.
Cambiaggi, C., Scupoli, M. T., Cestari, T., Gerosa, F., Carra, G., Tridente, G., Accolla, R. S. Constitutive expression of CD69 in interspecies T-cell hybrids and locus assignment to human chromosome 12. Immunogenetics 36: 117-120, 1992. [PubMed: 1612643] [Full Text: https://doi.org/10.1007/BF00215288]
Esplugues, E., Sancho, D., Vega-Ramos, J., Martinez-A, C., Syrbe, U., Hamann, A., Engel, P., Sanchez-Madrid, F., Lauzurica, P. Enhanced antitumor immunity in mice deficient in CD69. J. Exp. Med. 197: 1093-1106, 2003. [PubMed: 12732655] [Full Text: https://doi.org/10.1084/jem.20021337]
Lopez-Cabrera, M., Santis, A. G., Fernandez-Ruiz, E., Blacher, R., Esch, F., Sanchez-Mateos, P., Sanchez-Madrid, F. 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. J. Exp. Med. 178: 537-547, 1993. [PubMed: 8340758] [Full Text: https://doi.org/10.1084/jem.178.2.537]
Sancho, D., Gomez, M., Viedma, F., Esplugues, E., Gordon-Alonso, M., Garcia-Lopez, M. A., de la Fuente, H., Martinez-A, C., Lauzurica, P., Sanchez-Madrid, F. CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis. J. Clin. Invest. 112: 872-882, 2003. [PubMed: 12975472] [Full Text: https://doi.org/10.1172/JCI19112]
Shiow, L. R., Rosen, D. B., Brdickova, N., Xu, Y., An, J., Lanier, L. L., Cyster, J. G., Matloubian, M. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440: 540-544, 2006. [PubMed: 16525420] [Full Text: https://doi.org/10.1038/nature04606]