Preclinical model for the study of immune responses specific for a hepatic-self-antigen

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 ### Competing Interest Statement The authors have declared no competing interest. * 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