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.
