CEACAM1 controls immune-mediated liver injury by promoting IL-2-dependent Treg induction

Introduction:

Disturbance of the balance between regulatory T cells (Treg) and effector T cells and defects in Treg function can cause autoimmune liver disease. The cellular adhesion molecule Carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) is a checkpoint immune co-receptor that can suppress the activity of natural killer (NK), natural killer T (NKT) cells, conventional T cells (Tconv) and myeloid cells in various models of autoimmune disease, including experimental autoimmune encephalitis (EAE), ulcerative colitis, graft-versus-host disease but also in microbial infections. In the liver, Ceacam1 is expressed on hepatocytes and can have an anti-fibrotic effect in non-alcoholic steatohepatitis. Its role in immune-mediated hepatitis is unknown.

Objectives:

To reveal Ceacam1-dependent regulation of Treg homeostasis.

Methods:

In concanavalin A (ConA)-induced liver injury, plasma ALT and plasmatic and cell culture supernatant cytokine levels were analyzed by enzymatic tests and ELISA. Non-parenchymal, splenic cell populations and T cells from T cell/hepatocyte cocultures were characterized by flow cytometry. Adoptive transfers of CD4 T cells prior to ConA exposure were performed with wild type (WT) and Ceacam1 ^-/- donors and WT or Rag1 ^-/- recipients.

Results:

ConA-induced CD4 T cell-dependent liver injury was aggravated and persisted in Ceacam1-deficient mice. This was accompanied by a reduction in hepatic Treg frequencies, which showed an impaired response to IL-2, and reduction of signal transducer and activator of transcription (STAT)5 phosphorylation necessary for Treg conversion. Additionally, IL-2 production by Ceacam1-deficient CD4 T cells cultured with hepatocytes was significantly reduced and failed to support hepatocyte-induced Treg conversion. In adoptive transfers of WT and Ceacam1-deficient CD4 Tconv and/or Tregs into Rag1 ^-/- or WT recipients, we show that hepatic Treg cell expansion and in vivo suppressive activity depended on CD4 T cell and Treg-related Ceacam1 expression.

Conclusion:

Ceacam1 confers protection from T cell-mediated liver injury by augmenting IL-2 production and downstream phosphorylation of STAT5 by intrahepatic CD4 T cells, and thereby promotes Treg expansion and stability.