Abstract
The liver displays a strong capacity to induce tolerance toward hepatic antigens. However, hepatic tolerance can be overcome with the development of local autoimmune diseases such as autoimmune hepatitis (AIH). This chronic inflammatory disorder leads to a progressive destruction of liver parenchyma if non-treated. Although the CD4+ T cell response seems a key player of this immune disorder, the dynamics and biology of emerging liver antigen-specific CD4+ T cells are poorly described. Here, we developed a new murine model which mimics hepatic autoreactivity allowing the study and monitoring of antigen-specific CD4+ T cells from their emergence to local immune response. We show that the induction of the expression of an antigen in the liver in non-inflammatory condition leads to antigen tolerance. In inflammatory condition, using viral vector transduction, we observe the development of a complete adaptive immune response concomitant with the antigen expression in the liver. The presence of antigen-specific CD4+ T cells in the liver is associated to transient hepatic damages. Interestingly, the neo-antigen expression by hepatocytes after peripheral immunisation induces the recruitment of antigen-specific CD4+ T cells and hepatic damages. These data demonstrate that the recruitment of antigen-specific CD4+ T cells in the liver is conditioned by an immune coordination between surface antigen expression by hepatocytes and peripheral immune response and mimics the first step of a local autoreactive process. In the long-term, we observe that the hepatic environment has the capacity to control the local, but not the systemic, antigen-specific CD4+ T cells. Additional immune events might be involved in the long-term chronic immune reactivity in the liver, following the first steps described in this study.
Key points
Antigen expression in the liver in non-inflammatory condition leads to antigen tolerance
Antigen expression in the liver in immunization condition (concomitant or pre-existing) is sufficient to induce liver recruitment of antigen-specific CD4+ T cells and hepatic damages
This model mimics the first step of an autoreactive process against a liver antigen
In the long-term, the hepatic environment induces a local tolerance toward the antigen expression and the clearance of liver-infiltrating, but not peripheral, antigen-specific CD4+ T cells
This new murine model can be of interest for the analysis of the immunomodulatory pathways implicated in liver tolerization of autoreactive CD4+ T cells and identification of potential extrinsic factors implicated in an acute-to-chronic transition as observed during autoimmune hepatitis
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- AIH
- autoimmune hepatitis
- ALT
- alanine transaminase
- AST
- aspartate transaminase
- CYP2D6
- cytochrome P450 2D6
- FTCD
- Formiminotransferase cyclodeaminase
- HA
- hemagglutinin
- IgG
- immunoglobulin G
- i.m
- intramuscular
- i.v
- intravenous
- LC-1
- liver cytosol 1
- LKM-1
- liver kidney microsomal type 1
- MHC(-II)
- (class II) major histocompatibility complex
- NPCs
- non-parenchymal cells
- SLA
- soluble liver antigen
- Tregs
- regulatory T cells
- TTR
- transthyretin