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CEACAM1: contact-dependent control of immunity

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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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Figure 1: The carcinoembryonic antigen family and naturally occurring isoforms of human CEACAM1.
Figure 2: Dimerization of CEACAM1.
Figure 3: CEACAM receptor binding by pathogenic Neisseria spp.
Figure 4: Schematic depictions of a model for CEACAM1 function in T cells.

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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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Correspondence to Scott D. Gray-Owen.

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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.

CD16CD56+ 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 CD16CD56+ 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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