Key Points
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The carcinoembryonic-antigen-related cell-adhesion molecules (CEACAMs) are members of the immunoglobulin superfamily known to be involved in intercellular homophilic and heterophilic binding interactions that affect a wide array of normal and pathogenic processes related to cellular activation, proliferation and death, as well as being receptors for pathogenic bacteria and viruses.
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CEACAM1 is expressed by most immune cells, with its expression levels, surface localization and dimeric arrangement each being affected by cellular activation state. Differential splicing of the CEACAM1 transcript leads to the synthesis of multiple isoforms that differ in both extracellular and cytoplasmic domains, which changes their ability to undergo intercellular binding and intracellular signalling, respectively.
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Whereas CEACAM1 isoforms expressing a long (L) cytoplasmic tail inhibit signalling downstream of the T- and B-cell receptors, CEACAM1 isoforms expressing a short (S) cytoplasmic tail modify the co-inhibitory function of CEACAM1–L isoforms, indicating that the relative expression of L and S isoforms provides an ability to tune the inhibitory properties of this receptor.
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CEACAM1 functions as a MHC-class-I-independent inhibitory receptor on natural killer cells when ligated homophilically by CEACAM1 on target cells, such that overexpression of CEACAM1 on cancer cells might function as a means to avoid immune surveillance.
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CEACAM1 binding by bacterial and viral adhesins inhibits immune-cell function, thereby providing a means by which these pathogens might suppress specific immune responses to infection.
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Ligation of CEACAM1 homophilically (for example, using a CEACAM1–Fc fusion protein) or heterophilically (for example, using CEACAM1-specific monoclonal antibody) inhibits inflammation of the intestine and potentially other organs in animal models.
Abstract
The carcinoembryonic-antigen-related cell-adhesion molecule (CEACAM) family of proteins has been implicated in various intercellular-adhesion and intracellular-signalling-mediated effects that govern the growth and differentiation of normal and cancerous cells. Recent studies show that there is an important role for members of the CEACAM family in modulating the immune responses associated with infection, inflammation and cancer. In this Review, we consider the evidence for CEACAM involvement in immunity, with a particular emphasis on CEACAM1, which functions as a regulatory co-receptor for both lymphoid and myeloid cell types.
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References
Beauchemin, N. et al. Redefined nomenclature for members of the carcinoembryonic antigen family. Exp. Cell Res. 252, 243–249 (1999). Describes a unified nomenclature for the CEA family.
Benchimol, S. et al. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 57, 327–334 (1989).
Robitaille, J. et al. Comparison of expression patterns and cell adhesion properties of the mouse biliary glycoproteins Bbgp1 and Bbgp2. Eur. J. Biochem. 264, 534–544 (1999).
Oikawa, S. et al. A specific heterotypic cell adhesion activity between members of carcinoembryonic antigen family, W272 and NCA, is mediated by N-domains. J. Biol. Chem. 266, 7995–8001 (1991).
Stern, N. et al. Carcinoembryonic antigen (CEA) inhibits NK killing via interaction with CEA-related cell adhesion molecule 1. J. Immunol. 174, 6692–6701 (2005).
Wagener, C. & Ergun, S. Angiogenic properties of the carcinoembryonic antigen-related cell adhesion molecule 1. Exp. Cell Res. 261, 19–24 (2000). Provides the first evidence that CEACAM1 binding governs angiogenesis.
Najjar, S. M. Regulation of insulin action by CEACAM1. Trends Endocrinol. Metab. 13, 240–245 (2002).
Fournes, B., Sadekova, S., Turbide, C., Letourneau, S. & Beauchemin, N. The CEACAM1-L Ser503 residue is crucial for inhibition of colon cancer cell tumorigenicity. Oncogene 20, 219–230 (2001).
Kirshner, J., Chen, C. J., Liu, P., Huang, J. & Shively, J. E. CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture. Proc. Natl Acad. Sci. USA 100, 521–526 (2003). Provides one of the clearest demonstrations of active signalling by CEACAM1-S, and describes a role for this receptor in tissue morphogenesis.
Nittka, S., Gunther, J., Ebisch, C., Erbersdobler, A. & Neumaier, M. The human tumour suppressor CEACAM1 modulates apoptosis and is implicated in early colorectal tumorigenesis. Oncogene 23, 9306–9313 (2004).
Gray-Owen, S. D. Neisserial Opa proteins: impact on colonization, dissemination and immunity. Scand. J. Infect. Dis. 35, 614–618 (2003).
Hemmila, E. et al. Ceacam1a−/− mice are completely resistant to infection by murine coronavirus mouse hepatitis virus a59. J. Virol. 78, 10156–10165 (2004). Describes the first generation of mice containing a partial knockout of Ceacam1 , and shows the essential nature of CEACAM1 for infection by MHV.
Zebhauser, R. et al. Identification of a novel group of evolutionarily conserved members within the rapidly diverging murine CEA family. Genomics 86, 566–580 (2005). Describes the genome-sequence-based identification of new CEA-family members and the first analysis of the tissue distribution of these glycoproteins.
Kammerer, R., Hahn, S., Singer, B. B., Luo, J. S. & von Kleist, S. Biliary glycoprotein (CD66a), a cell adhesion molecule of the immunoglobulin superfamily, on human lymphocytes: structure, expression and involvement in T cell activation. Eur. J. Immunol. 28, 3664–3674 (1998).
Prall, F. et al. CD66a (BGP), an adhesion molecule of the carcinoembryonic antigen family, is expressed in epithelium, endothelium, and myeloid cells in a wide range of normal human tissues. J. Histochem. Cytochem. 44, 35–41 (1996).
Odin, P. & Öbrink, B. Quantitative determination of the organ distribution of the cell adhesion molecule cell-CAM 105 by radioimmunoassay. Exp. Cell Res. 171, 1–15 (1987).
Lucka, L. et al. Identification of Lewis x structures of the cell adhesion molecule CEACAM1 from human granulocytes. Glycobiology 15, 87–100 (2005).
Tan, K. et al. Crystal structure of murine sCEACAM1a[1,4]: a coronavirus receptor in the CEA family. EMBO J. 21, 2076–2086 (2002). Describes the crystal structure of mouse CEACAM1, including details of a fold unseen in other immunoglobulin-superfamily members.
Watt, S. M. et al. Homophilic adhesion of human CEACAM1 involves N-terminal domain interactions: structural analysis of the binding site. Blood 98, 1469–1479 (2001).
Edlund, M., Blikstad, I. & Öbrink, B. Calmodulin binds to specific sequences in the cytoplasmic domain of C-CAM and downregulates C-CAM self-association. J. Biol. Chem. 271, 1393–1399 (1996).
Schumann, D., Chen, C. J., Kaplan, B. & Shively, J. E. Carcinoembryonic antigen cell adhesion molecule 1 directly associates with cytoskeleton proteins actin and tropomyosin. J. Biol. Chem. 276, 47421–47433 (2001).
Singer, B. B., Scheffrahn, I. & Öbrink, B. The tumour growth-inhibiting cell adhesion molecule CEACAM1 (C-CAM) is differently expressed in proliferating and quiescent epithelial cells and regulates cell proliferation. Cancer Res. 60, 1236–1244 (2000).
Greicius, G., Severinson, E., Beauchemin, N., Öbrink, B. & Singer, B. B. CEACAM1 is a potent regulator of B cell receptor complex-induced activation. J. Leukoc. Biol. 74, 126–134 (2003).
Sundberg, U., Beauchemin, N. & Öbrink, B. The cytoplasmic domain of CEACAM1-L controls its lateral localization and the organization of desmosomes in polarized epithelial cells. J. Cell Sci. 117, 1091–1104 (2004). Shows that intracellular signalling events govern CEACAM1 cell-surface expression, apical versus basolateral compartmentalization and intercellular binding.
Hunter, I., Sawa, H., Edlund, M. & Öbrink, B. Evidence for regulated dimerization of cell-cell adhesion molecule (C-CAM) in epithelial cells. Biochem. J. 320, 847–853 (1996).
Öbrink, B. et al. Computational analysis of isoform-specific signal regulation by CEACAM1 — a cell adhesion molecule expressed in PC12 cells. Ann. N Y Acad. Sci. 971, 597–607 (2002).
Öbrink, B. CEA adhesion molecules: multifunctional proteins with signal-regulatory properties. Curr. Opin. Cell Biol. 9, 616–626 (1997).
Markel, G. et al. The critical role of residues 43R and 44Q of carcinoembryonic antigen cell adhesion molecules-1 in the protection from killing by human NK cells. J. Immunol. 173, 3732–3739 (2004).
Huber, M. et al. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. J. Biol. Chem. 274, 335–344 (1999).
Beauchemin, N. et al. Association of biliary glycoprotein with protein tyrosine phosphatase SHP-1 in malignant colon epithelial cells. Oncogene 14, 783–790 (1997).
Izzi, L., Turbide, C., Houde, C., Kunath, T. & Beauchemin, N. Cis-determinants in the cytoplasmic domain of CEACAM1 responsible for its tumour inhibitory function. Oncogene 18, 5563–5572 (1999). Provides genetic evidence that tyrosine residues in the ITIMs of CEACAM1 govern tumour-cell proliferation.
Coutelier, J. P. et al. B lymphocyte and macrophage expression of carcinoembryonic antigen-related adhesion molecules that serve as receptors for murine coronavirus. Eur. J. Immunol. 24, 1383–1390 (1994).
Iijima, H. et al. Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1. J. Exp. Med. 199, 471–482 (2004). First in vivo evidence of the immunosuppressive capacity of CEACAM1: CEACAM1-specific ligands reduce the severity of colitis in mice.
Nakajima, A. et al. Activation-induced expression of carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T lymphocyte function. J. Immunol. 168, 1028–1035 (2002).
Thompson, C. B. & Allison, J. P. The emerging role of CTLA-4 as an immune attenuator. Immunity 7, 445–450 (1997).
Moller, M. J., Kammerer, R., Grunert, F. & von Kleist, S. Biliary glycoprotein (BGP) expression on T cells and on a natural-killer-cell sub-population. Int. J. Cancer 65, 740–745 (1996). First demonstration of CEACAM1 expression on activated lymphocyte populations.
Morales, V. M. et al. Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a). J. Immunol. 163, 1363–1370 (1999).
Boulton, I. C. & Gray-Owen, S. D. Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nature Immunol. 3, 229–236 (2002). First demonstration that bacterial adhesins that bind CEACAM1 can suppress immune-cell responses to various activating stimuli.
Donda, A. et al. Locally inducible CD66a (CEACAM1) as an amplifier of the human intestinal T cell response. Eur. J. Immunol. 30, 2593–2603 (2000).
Chen, C. J. & Shively, J. E. The cell–cell adhesion molecule carcinoembryonic antigen-related cellular adhesion molecule 1 inhibits IL-2 production and proliferation in human T cells by association with Src homology protein-1 and downregulates IL-2 receptor. J. Immunol. 172, 3544–3552 (2004).
Singer, B. B. et al. Carcinoembryonic antigen-related cell adhesion molecule 1 expression and signalling in human, mouse, and rat leukocytes: evidence for replacement of the short cytoplasmic domain isoform by glycosylphosphatidylinositol-linked proteins in human leukocytes. J. Immunol. 168, 5139–5146 (2002).
Turbide, C., Kunath, T., Daniels, E. & Beauchemin, N. Optimal ratios of biliary glycoprotein isoforms required for inhibition of colonic tumour cell growth. Cancer Res. 57, 2781–2788 (1997).
Chen, D. et al. Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and co-stimulate human T cell function. J. Immunol. 172, 3535–3543 (2004).
Markel, G. et al. Pivotal role of CEACAM1 protein in the inhibition of activated decidual lymphocyte functions. J. Clin. Invest. 110, 943–953 (2002).
Edlund, M. & Öbrink, B. Evidence for calmodulin binding to the cytoplasmic domains of two C-CAM isoforms. FEBS Lett. 327, 90–94 (1993).
Chen, T. et al. Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals. J. Leukoc. Biol. 70, 335–340 (2001).
Scheffrahn, I., Singer, B. B., Sigmundsson, K., Lucka, L. & Öbrink, B. Control of density-dependent, cell state-specific signal transduction by the cell adhesion molecule CEACAM1, and its influence on cell cycle regulation. Exp. Cell Res. 307, 427–435 (2005).
Markel, G. et al. The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients. Blood 103, 1770–1778 (2004).
Markel, G. et al. CD66a interactions between human melanoma and NK cells: a novel class I MHC-independent inhibitory mechanism of cytotoxicity. J. Immunol. 168, 2803–2810 (2002). First demonstration that CEACAM1 expression protects from killing by NK cells through trans -homophilic interactions between CEACAM1 on the effector and target cells.
Moretta, L. & Moretta, A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. 23, 255–259 (2004).
Markel, G. et al. Biological function of the soluble CEACAM1 protein and implications in TAP2-deficient patients. Eur. J. Immunol. 34, 2138–2148 (2004).
Thies, A. et al. CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J. Clin. Oncol. 20, 2530–2536 (2002).
Ebrahimnejad, A. et al. CEACAM1 enhances invasion and migration of melanocytic and melanoma cells. Am. J. Pathol. 165, 1781–1787 (2004).
Svenberg, T., Wahren, B. & Hammarstrom, S. Elevated serum levels of a biliary glycoprotein (BGPI) in patients with liver or biliary tract disease. Clin. Exp. Immunol. 36, 317–325 (1979).
Budt, M., Michely, B., Muller, M. M., Reutter, W. & Lucka, L. Secreted CEACAM1 splice variants in rat cell lines and in vivo in rat serum. Biochem. Biophys. Res. Commun. 292, 749–755 (2002).
Draberova, L. et al. Soluble isoforms of CEACAM1 containing the A2 domain: increased serum levels in patients with obstructive jaundice and differences in 3-fucosyl-N-acetyl-lactosamine moiety. Immunology 101, 279–287 (2000).
Stocks, S. C. & Kerr, M. A. Neutrophil NCA-160 (CD66) is the major protein carrier of selectin binding carbohydrate groups LewisX and sialyl lewisX. Biochem. Biophys. Res. Commun. 195, 478–483 (1993).
Kuroki, M., Matsuo, Y., Kinugasa, T. & Matsuoka, Y. Augmented expression and release of nonspecific crossreacting antigens (NCAs), members of the CEA family, by human neutrophils during cell activation. J. Leuko. Biol. 52, 551–557 (1992).
Kuijpers, T. W., van der Schoot, C. E., Hoogerwerf, M. & Roos, D. Crosslinking of the carcinoembryonic antigen-like glycoproteins CD66 and CD67 induces neutrophil aggregation. J. Immunol. 151, 4934–4940 (1993).
Kuijpers, T. W. et al. CD66 nonspecific crossreacting antigens are involved in neutrophil adherence to cytokine-activated endothelial cells. J. Cell Biol. 118, 457–466 (1992).
Stocks, S. C. et al. CD66: role in the regulation of neutrophil effector function. Eur. J. Immunol. 26, 2924–2932 (1996).
Muenzner, P., Rohde, M., Kneitz, S. & Hauck, C. R. CEACAM engagement by human pathogens enhances cell adhesion and counteracts bacteria-induced detachment of epithelial cells. J. Cell Biol. 170, 825–836 (2005). Shows that bacterial binding to CEACAMs prevents infection-induced epithelial-cell detachment from the extracellular matrix by an integrin-dependent process.
Gray-Owen, S. D., Lorenzen, D. R., Haude, A., Meyer, T. F. & Dehio, C. Differential Opa specificities for CD66 receptors influence tissue interactions and cellular response to Neisseria gonorrhoeae. Mol. Microbiol. 26, 971–980 (1997).
Singer, B. B. et al. CEACAM1 (CD66a) mediates delay of spontaneous and Fas ligand-induced apoptosis in granulocytes. Eur. J. Immunol. 35, 1949–1959 (2005).
Kammerer, R., Stober, D., Singer, B. B., Öbrink, B. & Reimann, J. Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J. Immunol. 166, 6537–6544 (2001). Shows that DCs express CEACAM1 and provides the first indication that CEACAM1-specific ligands affect the ability of a DC to influence the size and polarity of T-cell responses.
Dhodapkar, K. M. et al. Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumour cells. Proc. Natl Acad. Sci. USA 102, 2910–2915 (2005).
Genovese, M. C. et al. Abatacept for rheumatoid arthritis refractory to tumour necrosis factor α inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).
Rosenberg, M. et al. The expression of mouse biliary glycoprotein, a carcinoembryonic antigen-related gene, is downregulated in malignant mouse tissues. Cancer Res. 53, 4938–4945 (1993).
Nollau, P. et al. Expression of CD66a (human C-CAM) and other members of the carcinoembryonic antigen gene family of adhesion molecules in human colorectal adenomas. Cancer Res. 57, 2354–2357 (1997).
Neumaier, M., Paululat, S., Chan, A., Matthaes, P. & Wagener, C. Biliary glycoprotein, a potential human cell adhesion molecule, is downregulated in colorectal carcinomas. Proc. Natl Acad. Sci. USA 90, 10744–10748 (1993). One of the first studies showing that CEACAM1 expression is downregulated on tumour cells.
Bamberger, A. M. et al. Dysregulated expression of CD66a (BGP, C-CAM), an adhesion molecule of the CEA family, in endometrial cancer. Am. J. Pathol. 152, 1401–1406 (1998).
Riethdorf, L. et al. Differential expression of CD66a (BGP), a cell adhesion molecule of the carcinoembryonic antigen family, in benign, premalignant, and malignant lesions of the human mammary gland. J. Histochem. Cytochem. 45, 957–963 (1997).
Hsieh, J. T. et al. Tumour suppressive role of an androgen-regulated epithelial cell adhesion molecule (C-CAM) in prostate carcinoma cell revealed by sense and antisense approaches. Cancer Res. 55, 190–197 (1995). Shows that CEACAM1 expression inhibits tumour formation, and that downregulated CEACAM1 expression promotes tumorigenicity.
Kunath, T., Ordonez-Garcia, C., Turbide, C. & Beauchemin, N. Inhibition of colonic tumour cell growth by biliary glycoprotein. Oncogene 11, 2375–2382 (1995).
Laack, E. et al. Expression of CEACAM1 in adenocarcinoma of the lung: a factor of independent prognostic significance. J. Clin. Oncol. 20, 4279–4284 (2002).
Sienel, W. et al. Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 promotes progression of non-small cell lung cancer. Clin. Cancer Res. 9, 2260–2266 (2003).
Kinugasa, T. et al. Expression of four CEA family antigens (CEA, NCA, BGP and CGM2) in normal and cancerous gastric epithelial cells: upregulation of BGP and CGM2 in carcinomas. Int. J. Cancer 76, 148–153 (1998).
Kammerer, R. & von Kleist, S. CEA expression of colorectal adenocarcinomas is correlated with their resistance against LAK-cell lysis. Int. J. Cancer 57, 341–347 (1994).
Kammerer, R. & von Kleist, S. The carcinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes. Int. J. Cancer 68, 457–463 (1996).
McGee, Z. A., Stephens, D. S., Hoffman, L. H., Schlech, W. F. & Horn, R. G. Mechanisms of mucosal invasion by pathogenic Neisseria. Rev. Infect. Dis. 5 (Suppl. 4), S708–S714 (1983).
Wang, J., Gray-Owen, S. D., Knorre, A., Meyer, T. F. & Dehio, C. Opa binding to cellular CD66 receptors mediates the transcellular traversal of Neisseria gonorrhoeae across polarised T84 epithelial cell monolayers. Mol. Microbiol. 30, 657–671 (1998).
Hedges, S. R., Sibley, D. A., Mayo, M. S., Hook, E. W. & Russell, M. W. Cytokine and antibody responses in women infected with Neisseria gonorrhoeae: effects of concomitant infections. J. Infect. Dis. 178, 742–751 (1998).
Hedges, S. R., Mayo, M. S., Mestecky, J., Hook, E. W. & Russell, M. W. Limited local and systemic antibody responses to Neisseria gonorrhoeae during uncomplicated genital infections. Infect. Immun. 67, 3937–3946 (1999).
Pettit, R. K. & Judd, R. C. Characterization of naturally elaborated blebs from serum-susceptible and serum-resistant strains of Neisseria gonorrhoeae. Mol. Microbiol. 6, 723–728 (1992).
Namork, E. & Brandtzaeg, P. Fatal meningococcal septicaemia with 'blebbing' meningococcus. Lancet 360, 1741 (2002).
Pantelic, M. et al. Neisseria gonorrhoeae kills carcinoembryonic antigen-related cellular adhesion molecule 1 (CD66a)-expressing human B cells and inhibits antibody production. Infect. Immun. 73, 4171–4179 (2005).
Kruse, M. et al. Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J. Virol. 74, 7127–7136 (2000).
Senechal, B., Boruchov, A. M., Reagan, J. L., Hart, D. N. & Young, J. W. Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103, 4207–4215 (2004).
Olsson, H., Wikstrom, K., Kjellstrom, G. & Öbrink, B. Cell adhesion activity of the short cytoplasmic domain isoform of C-CAM (C-CAM2) in CHO cells. FEBS Lett. 365, 51–56 (1995).
Oikawa, S., Kuroki, M., Matsuoka, Y., Kosaki, G. & Nakazato, H. Homotypic and heterotypic Ca++-independent cell adhesion activities of biliary glycoprotein, a member of carcinoembryonic antigen family, expressed on CHO cell surface. Biochem. Biophys. Res. Commun. 186, 881–887 (1992).
Schwartz, J. C., Zhang, X., Fedorov, A. A., Nathenson, S. G. & Almo, S. C. Structural basis for co-stimulation by the human CTLA-4/B7–2 complex. Nature 410, 604–608 (2001).
Sippel, C. J., Fallon, R. J. & Perlmutter, D. H. Bile acid efflux mediated by the rat liver canalicular bile acid transport/ecto-ATPase protein requires serine 503 phosphorylation and is regulated by tyrosine 488 phosphorylation. J. Biol. Chem. 269, 19539–19545 (1994).
Poy, M. N. et al. CEACAM1 regulates insulin clearance in liver. Nature Genet. 30, 270–276 (2002). Provides striking in vivo evidence that CEACAM1 has an important role in normal insulin metabolism.
Bradshaw, J. D. et al. Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated protein is negatively regulated by tyrosine phosphorylation. Biochemistry 36, 15975–15982 (1997).
Abraham, R. T. & Weiss, A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nature Rev. Immunol. 4, 301–308 (2004).
Sadekova, S., Lamarche-Vane, N., Li, X. & Beauchemin, N. The CEACAM1-L glycoprotein associates with the actin cytoskeleton and localizes to cell–cell contact through activation of Rho-like GTPases. Mol. Biol. Cell 11, 65–77 (2000).
Fournes, B., Farrah, J., Olson, M., Lamarche-Vane, N. & Beauchemin, N. Distinct Rho GTPase activities regulate epithelial cell localization of the adhesion molecule CEACAM1: involvement of the CEACAM1 transmembrane domain. Mol. Cell. Biol. 23, 7291–7304 (2003).
Veillette, A., Latour, S. & Davidson, D. Negative regulation of immunoreceptor signalling. Annu. Rev. Immunol. 20, 669–707 (2002).
Zhang, L., Lorenz, U. & Ravichandran, K. S. Role of Shc in T-cell development and function. Immunol. Rev. 191, 183–195 (2003).
Abou-Rjaily, G. A. et al. CEACAM1 modulates epidermal growth factor receptor-mediated cell proliferation. J. Clin. Invest. 114, 944–952 (2004).
Leo, A. & Schraven, B. Adapters in lymphocyte signalling. Curr. Opin. Immunol. 13, 307–316 (2001).
Teglund, S., Olsen, A., Khan, W. N., Frangsmyr, L. & Hammarstrom, S. The pregnancy-specific glycoprotein (PSG) gene cluster on human chromosome 19: fine structure of the 11 PSG genes and identification of 6 new genes forming a third subgroup within the carcinoembryonic antigen (CEA) family. Genomics 23, 669–684 (1994).
McLellan, A. S. et al. Structure and evolution of the mouse pregnancy-specific glycoprotein (Psg) gene locus. BMC Genomics 6, 4 (2005).
Lin, T. M., Halbert, S. P. & Spellacy, W. N. Measurement of pregnancy-associated plasma proteins during human gestation. J. Clin. Invest. 54, 576–582 (1974).
Anthony, F., Masson, G. M. & Wood, P. J. Development of a radioimmunoassay for pregnancy-associated plasma protein A and establishment of normal levels in the first trimester of pregnancy. Ann. Clin. Biochem. 20, 26–30 (1983).
Gordon, Y. P., Grudzinskas, J. G., Jeffrey, D. & Chard, T. Concentrations of pregnancy-specific β1–glycoprotein in maternal blood in normal pregnancy and in intrauterine growth retardation. Lancet 1, 331–333 (1977).
Hau, J., Gidley-Baird, A. A., Westergaard, J. G. & Teisner, B. The effect on pregnancy of intrauterine administration of antibodies against two pregnancy-associated murine proteins: murine pregnancy-specific β1-glycoprotein and murine pregnancy-associated α2-glycoprotein. Biomed. Biochim. Acta 44, 1255–1259 (1985).
Wessells, J. et al. Pregnancy specific glycoprotein 18 induces IL-10 expression in murine macrophages. Eur. J. Immunol. 30, 1830–1840 (2000).
Ha, C. T., Waterhouse, R., Wessells, J., Wu, J. A. & Dveksler, G. S. Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE2, and TGF-β1. J. Leukoc. Biol. 77, 948–957 (2005).
McCaw, S. E., Schneider, J., Liao, E. H., Zimmermann, W. & Gray-Owen, S. D. Immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation during engulfment of Neisseria gonorrhoeae by the neutrophil-restricted CEACAM3 (CD66d) receptor. Mol. Microbiol. 49, 623–637 (2003).
Schmitter, T., Agerer, F., Peterson, L., Munzner, P. & Hauck, C. R. Granulocyte CEACAM3 is a phagocytic receptor of the innate immune system that mediates recognition and elimination of human-specific pathogens. J. Exp. Med. 199, 35–46 (2004).
Naids, F. L. & Rest, R. F. Stimulation of human neutrophil oxidative metabolism by nonopsonized Neisseria gonorrhoeae. Infect. Immun. 59, 4383–4390 (1991).
Booth, J. W. et al. Phosphatidylinositol 3-kinases in CEACAM-mediated internalization of Neisseria gonorrhoeae. J. Biol. Chem. 278, 14037–14045 (2003).
Billker, O. et al. Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and independent pathways. EMBO J. 21, 560–571 (2002).
Botelho, R. J., Scott, C. C. & Grinstein, S. Phosphoinositide involvement in phagocytosis and phagosome maturation. Curr. Top. Microbiol. Immunol. 282, 1–30 (2004).
Virji, M., Makepeace, K., Ferguson, D. J. P. & Watt, S. Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic neisseriae. Mol. Microbiol. 22, 941–950 (1996).
Bos, M. P., Grunert, F. & Belland, R. J. Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae. Infect. Immun. 65, 2353–2361 (1997).
Chen, T., Grunert, F., Medina-Marino, A. & Gotschlich, E. C. Several carcinoembryonic antigens (CD66) serve as receptors for gonococcal opacity proteins. J. Exp. Med. 185, 1557–1564 (1997).
Muenzner, P. et al. Carcinoembryonic antigen family receptor specificity of Neisseria meningitidis Opa variants influences adherence to and invasion of proinflammatory cytokine-activated endothelial cells. Infect. Immun. 68, 3601–3607 (2000).
de Vries, F. P., Cole, J., Dankert, J., Frosch, M. & van Putten, J. P. M. Neisseria meningitidis producing the Opc adhesin binds epithelial cell proteogylcan receptors. Mol. Microbiol. 27, 1203–1212 (1998).
Toleman, M., Aho, E. & Virji, M. Expression of pathogen-like Opa adhesins in commensal Neisseria: genetic and functional analysis. Cell. Microbiol. 3, 33–44 (2001).
Hill, D. J. et al. The variable P5 proteins of typeable and non-typeable Haemophilus influenzae target human CEACAM1. Mol. Microbiol. 39, 850–862 (2001).
Virji, M. et al. Carcinoembryonic antigens are targeted by diverse strains of typable and non-typable Haemophilus influenzae. Mol. Microbiol. 36, 784–795 (2000).
Leusch, H. G. et al. Escherichia coli of human origin binds to carcinoembryonic antigen (CEA) and nonspecific crossreacting antigen (NCA). FEBS Lett. 261, 405–409 (1990).
Leusch, H. G., Drzeniek, Z., Markos-Pusztai, Z. & Wagener, C. Binding of Escherichia coli and Salmonella strains to members of the carcinoembryonic antigen family: differential binding inhibition by aromatic α-glycosides of mannose. Infect. Immun. 59, 2051–2057 (1991).
Berger, C. N., Billker, O., Meyer, T. F., Servin, A. L. & Kansau, I. Differential recognition of members of the carcinoembryonic antigen family by Afa/Dr adhesins of diffusely adhering Escherichia coli (Afa/Dr DAEC). Mol. Microbiol. 52, 963–983 (2004).
Acknowledgements
We thank our excellent colleagues in the community of CEACAM researchers who have contributed both directly and indirectly to this work. We thank J. Bluestone, R. Kammerer and W. Zimmermann for critical comments on the manuscript. S.D.G.-O. is supported by the Canadian Institutes for Health Research (CIHR), the Ontario HIV Treatment Network, the Province of Ontario and the McLaughlin Center for Molecular Medicine. R.S.B. is supported by the National Institutes of Health, USA, the United States–Israel Binational Science Foundation and the Harvard Digestive Diseases Center.
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R.S.B. is a scientific advisor to GenPat77 Pharmaceuticals, Inc., Berlin, Germany, which is developing CEACAM1 therapeutics.
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Glossary
- Orthologues
-
Homologous genes in different species, the lineages of which derive from a common ancestral gene without gene duplication or horizontal transmission.
- IgV-like domain
-
A protein domain that shows evolutionary similarity, in both linear sequence and folded (tertiary) structure, to the domains of the variable region of immunoglobulins. The domain folds into a sandwich of two β-pleated sheets consisting of anti-parallel β-strands. IgV-like domains differ from immunoglobulin constant-region type 2 (IgC2)-like domains in the number of β-strands in the β-pleated sheets.
- IgC2-like domain
-
A protein domain that shows evolutionary similarity, in both linear sequence and folded (tertiary) structure, to the immunoglobulin constant-region-type-2 (IgC2) domains. The domain folds into a sandwich of two β-pleated sheets consisting of anti-parallel β-strands. IgC2-like domains differ from domains of the variable region of immunoglobulins in the number of β-strands in the β-pleated sheets.
- Immunoreceptor tyrosine-based inhibitory motif
-
(ITIM). A short peptide motif that contains tyrosine residues and is found in the cytoplasmic tails of several inhibitory receptors. The prototype six-amino-acid ITIM sequence is (I/V/L/S)XYXX(L/V), with X denoting any amino acid. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family protein tyrosine kinases, and this provides a docking site for the recruitment of cytoplasmic phosphatases that have an SRC homology 2 (SH2) domain.
- Apical surface
-
The region of the plasma membrane of polarized epithelial cells that abuts a luminal surface.
- Basolateral surface
-
The region of the plasma membrane of polarized epithelial cells that abuts the basement membrane.
- Anti-parallel
-
An arrangement whereby two molecules are situated in parallel, head-to-tail fashion.
- Lamina propria
-
Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.
- Immunological synapse
-
A region that can form between two cells of the immune system that are in close contact, so named because of its similarities to the synapses that occur in the nervous system. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.
- FcγRIIB
-
A receptor with low binding affinity for the Fc domain of IgG, and that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic domain. It is postulated to inhibit B-cell activation in the presence of high concentrations of antibody.
- Immunoglobulin class switching
-
DNA rearrangement of the gene segment encoding the variable region of IgM to any of the IgG, IgA and IgE constant genes at the heavy-chain locus. Recombination occurs in repetitive sequences of DNA located upstream of each constant gene.
- CD16−CD56+ NK cells
-
Natural killer (NK) cells expressing surface CD56 but not CD16 (also known as FcγRIII). These cells represent a minor fraction of total NK cells in blood but a major fraction in tissues and secondary lymphoid organs. They tend to have relatively lower cytotoxic abilities but enhanced cytokine responsiveness and interferon-γ secretion capabilities than CD16+CD56+ NK cells, and they are thought to be important in regulation and priming of immune responses.
- CD16+CD56+ NK cells
-
NK cells expressing both CD56 and CD16. These cells represent the majority of peripheral blood NK cells and are preferentially recruited to sites of inflammation. They are more cytotoxic than CD16−CD56+ NK cells.
- Obstructive liver disease
-
Disease in which outflow of fluids from the apical surface of a hepatocyte (canalicular surface) is obstructed.
- FcγRIIA
-
A receptor that binds the Fc domain of IgG with low affinity. The carboxy-terminal cytoplasmic domain contains an immunoreceptor tyrosine-based activation motif (ITAM), which becomes phosphorylated following receptor aggregation, triggering the phagocytic engulfment of immunoglobulin-coated particles.
- Transcytose
-
The process of moving macromolecular cargo from one surface to another of a polarized epithelial cell.
- Isogenic strains
-
Bacterial strains that are genetically identical or that contain defined changes but are otherwise identical. For example, isogenic mutants typically refers to two strains that are identical except that one contains a defined mutation in a known protein.
- Outer membrane vesicles
-
'Blebs' of outer membrane liberated either naturally or through detergent extraction from Gram-negative bacteria. Typically being of ∼100 nm in diameter, their composition reflects the outer membrane of the bacterium from which they are produced, including the presence of bacterial endotoxin, lipids and proteins.
- Immunoreceptor tyrosine-based activation motif
-
(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tails of several signalling molecules. The amino-acid sequence of an ITAM is (D/E)XXYXX(L/I)X6–8YXX(L/I), with X denoting any amino acid. It is tyrosine phosphorylated after engagement of the ligand-binding subunits, which triggers a cascade of intracellular events that results in cellular activation.
- Steric hindrance
-
Physical blocking of interaction between two molecules.
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Gray-Owen, S., Blumberg, R. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol 6, 433–446 (2006). https://doi.org/10.1038/nri1864
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DOI: https://doi.org/10.1038/nri1864
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