CEACAM1 controls IL-2-dependent regulatory T cell induction in immune-mediated hepatitis

Abstract

A dysbalance between effector T cells (Tconv) and regulatory T cells (Tregs) and impaired Tregs function can cause autoimmune liver disease. Therefore, it is important to identify molecular mechanisms that control Treg homeostasis. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is an immune co-receptor with dichotomous roles in T cell regulation: its short isoform (CEACAM1S) can activate T cells and induce Tregs, whereas its long isoform (CEACAM1L) containing two intracellular immune receptor tyrosine-based inhibitory motifs (ITIMs), can inhibit activated T cell function. In the liver, CEACAM1 has anti-fibrotic effects in models of non-alcoholic steatohepatitis. However, its role in immune-mediated hepatitis is unknown. In the mouse model of concanavalin A (ConA)-induced CD4⁺ T cell-dependent liver injury, liver damage was aggravated and persisted in Ceacam1^-/- mice. Concomitantly, we observed hyperexpansion of Tconv, but reduction of IL-2 production and hepatic Foxp3⁺CD4⁺ Treg numbers. CEACAM1^-/-CD4⁺ T cells showed impaired IL-2-mediated signal transducer and activator of transcription (STAT)5 phosphorylation, which correlated with a failure of naïve CEACAM1^-/-CD4⁺ T cell to convert into Tregs in vitro. Furthermore, CEACAM1^-/- Tregs expressed reduced levels of Foxp3, CD25 and Bcl-2. Adoptive transfer experiments demonstrated that hepatic Treg expansion and suppressive activity required CEACAM1 expression on both CD4⁺ T cells and Tregs. We identified predominant CEACAM1S expression on hepatic CD4⁺ T cells and Tregs from mice with acute liver injury and expression of both isoforms in liver-derived CD4⁺ T cell clones from patients with liver injury. Conclusion: Our data suggest that CEACAM1S expression in CD4⁺ T cells augments IL-2 production and STAT5 phosphorylation leading to enhanced Treg induction and stability which ultimately confers protection from T cell-mediated liver injury. This article is protected by copyright. All rights reserved.

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