CEACAM1 and the regulation of mucosal inflammation

Abstract

Inflammatory bowel disease (IBD) is characterized by unrestrained T-cell activation that results in the production of a variety of inflammatory cytokines and other mediators. Understanding the mechanisms of T-cell regulation is therefore of significant importance to IBD and other forms of dysregulated-mucosal inflammation. An area that is of significant interest are the cell autonomous mechanisms of T-cell regulation through proteins that have natural inhibitory functions when expressed on T lymphocytes. One such molecule is carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). CEACAM1 is primarily an activation-induced cell-surface molecule that functions as a co-inhibitory receptor. Homophilic ligation of CEACAM1 on T cells leads to a signaling mechanism, which results in inhibition of a broad range T-cell functions. CEACAM1 therefore represents a new potential therapeutic target in the treatment of IBD.

Figure 1

Summary of CEACAM family members (adapted from ref. 14). Human CEACAM family members are encoded on chromosome 19. They include the CEA-related members (CEACAM5) and pregnancy-specific glycoproteins (PSG). The latter are soluble proteins. Each member consists of a membrane distal IgV-related N-domain and a variable number of IgGC2-related domains that are either linked to the membrane by a transmembrane anchor or glycophosphatidyl-linked anchor. Rodents (mouse and rat) only express CEACAM1. Please see the text for details.

Figure 2

Summary of CEACAM1 splice products (adapted from ref. 14). The single CEACAM1 gene in humans and rodents is characterized by alternate splicing, generating 11 isoforms in humans and four isoforms in mice. The nomenclature is adapted from ref. and described in the text. Splice variants that are in boxes are those that have been identified in human and mouse T cells by PCR. The schematic shows the predicted structure of a CEACAM1-4L splice variant with four extracellular domains and a long cytoplasmic tail containing two ITIM domains.

Figure 3

Inhibition of antigen-specific T-cell activation by CEACAM1 expressing a long cytoplasmic tail. CEACAM1-4L-transgenic mice (as described in ref. 21) were crossed with OT-II transgenic mice expressing a T-cell receptor specific for ovalbumin (OVA) in the context of I-A^d. T cells from these mice were exposed to different concentration of OVA in the context of wild-type antigen-presenting cells from Balb/c mice and activation assessed.