W137 - Peripheral Priming Is Required for Liver-Antigen-Specific TIGIT+ PD-1+ T Cell Accumulation in the Tissue

Abstract Text:

Purpose: In autoimmune hepatitis (AIH), the alteration of the hepatic tolerance is linked to an accumulation of autoreactive T cells. However, studying the emergence and biology of these T cells is technically challenging. The objective of this work was to decipher immune events involved in initiation and regulation of local hepatocellular-antigen-specific immune response.

Methods: We developed a murine model, in which the model antigen hemagglutinin (HA) expression is inducible and restricted to hepatocytes, thanks to the Cre-Lox recombination system. Liver HA expression was induced through intravenous injection of Cre-coding adenovirus (Ad Cre) or tamoxifen treatment. Peripheral immunization was obtained by intramuscular injection of Ad Cre or HA-coding plasmid. HA-specific T cells were tracked and characterized through tetramer staining, flow cytometry and RNA-sequencing. Immuno-phenotyping of blood memory T cells from AIH patients was performed by spectral cytometry.

Results: Local inflammatory signals are not sufficient to initiate adaptive immune response against HA when expressed in the liver. HA-specific T cell recruitment in the liver depends on peripheral priming combined with local antigen expression. Liver-antigen-specific T cell reactivity is marked by TIGIT and PD-1 co-expression. In AIH patients, the frequency of circulating PD-1+TIGIT+HLA-DR+ T cells correlates with AIH disease activity.

Conclusion: Our findings reveal a key connection between the liver and the periphery in hepatocellular-antigen-specific responses. TIGIT and PD-1 co-expression by T cells is a marker reflecting local T cell reactivity. Their presence in the blood of AIH patients suggests recirculation of autoreactive T cells and provides new biomarkers and therapeutic perspectives.