Soluble CEACAM1 induces activation of STAT5, Foxp3 expression and proliferation of Tregs in DC- T cell cocultures

Introduction:

CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) is a homophilic and heterophilic adhesion molecule that acts as an immune co-receptor on leukocytes. Soluble CEACAM1 (sCC1) was originally discovered as a serum marker in human patients with cholestasis and autoimmune liver disease. In murine immune-mediated hepatitis (Concanavalin A-induced hepatitis), CEACAM1 promotes IL-2-dependent Treg induction and stability, and Ceacam1 ^-/- mice exhibit hyperinflammation and persistence of liver injury. This immune-regulatory function requires tight regulation of CEACAM1 isoform expression; on CD4⁺ T cells, CEACAM1-S, the activatory isoform with a short cytoplasmic domain, fosters cytokine production and Treg induction. Contrary, its inhibitory isoform with two ITIMs and a long cytoplasmic tail (CEACAM1-L) interacts with co-inhibitory immune receptors (e.g. TIM-3) and limits activation.

Objectives:

The role of CEACAM1-ligation in hepatic immune regulation is unknown. The role of soluble CEACAM1/sCC1 in co-cultures of CD4⁺ T cells and antigen-presenting cells (dendritic cells, DCs) for T cell activation and Treg induction is investigated.

Materials & methods:

In sera from human patients and mice, soluble CEACAM1 was detected by Western Blot. Cocultures from bone-marrow derived, FACS-sorted DCs and MACS-sorted T cells from CEACAM1-deficient and WT mice were analyzed by FACS, and cytokines were quantified by bead-based immunoassays and ELISAs.

Results:

CEACAM1 is detectable in sera of patients with advanced primary sclerosing cholangitis (PSC), and in sera of WT mice. In cocultures of CD4⁺ T cells and dendritic cells, addition of sCC1 inhibits production of IL-2 by CD4⁺ T cells and IL-12 by DCs, regardless of their CEACAM1 expression status. sCC1 strongly binds to DC-activated CD4⁺CD25⁺ T cells which results in phosphorylation of STAT5 and upregulation of Foxp3.

Conclusion:

sCC1 binds to activated T cells and induces STAT5 signaling and Foxp3⁺ Tregs. On DCs, sCC1 binds to a heterophilic ligand, which leads to reduction of IL-12 production. This immunomodulatory function of (s) CEACAM1 will be further explored in vivo.