Dissecting cell-specific CEACAM1 expression on immune cells in hepatic immune regulation

Autoimmune hepatitis results from a quantitative or functional imbalance between pro-inflammatory effector T cells and anti-inflammatory regulatory T cells (Treg) in the liver. CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) is a member of the glycoprotein CEA family and it is expressed by T cells, natural killer (NK) cells, as well as antigen-presenting cells. CEACAM1 acts as an immune co-receptor and a homophilic and heterophilic adhesion molecule; its two major isoforms with either a long (CEACAM1-L) or a short (CEACAM1-S) cytoplasmic tail control T cell activation. The long isoform contains two ITIMs (immunoreceptor tyrosine-based inhibitory motifs) and inhibits T cell receptor activation and inflammatory cytokine production via binding of the tyrosine phosphatase SHP-1. In contrast, the short isoform without the ITIMs acts as an independent T cell activator. Previously, we have shown that CEACAM1 expression in CD4+T cells augments IL-2 production, which is crucial for hepatic Treg induction and expansion. Ceacam1knockout mice show exacerbation in a mouse model for autoimmune hepatitis as a result of inappropriate expansion of T effector cells and concomitant reduction in Tregs. In the serum of human patients with obstructive or autoimmune liver disease, soluble CEACAM1 is elevated and could act as a modulator of the hepatic immune response. However, the functional relevance of CEACAM1-CEACAM1-interactions in hepatic immune regulation has not been defined so far.