Accumulation of PD-1+ TIGIT+ T cells in the liver after local antigen reactivity and during autoimmune hepatitis

Guinebretiere, T.; Cardon, A.; Judor, J.-P.; Gavlovsky, P.-J.; Roux, F.; Huchet, V.; Chevalier, C.; Khaldi, M.; Bardou-Jacquet, E.; Elkrief, L.; Lannes, A.; Silvain, C.; Schnee, M.; Tanne, F.; Lemoinne, S.; De Martin, E.; Vavasseur, F.; Nicot, A.; Brouard, S.; Mosnier, J.-F.; Gournay, J.; Conchon, S.; Renand, A.

doi:10.1101/2025.08.29.672936

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bioRxiv · 10.1101/2025.08.29.672936

Accumulation of PD-1+ TIGIT+ T cells in the liver after local antigen reactivity and during autoimmune hepatitis

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Abstract

In autoimmune hepatitis (AIH), hepatocellular damage is linked to an accumulation of autoreactive T cells in the liver of patients, but how these cells emerge in the tissue remains unclear. Here we used a mouse model based on recombination-dependent inducible expression of influenza A hemagglutinin (HA) by hepatocytes to investigate initiation of liver antigen-specific response. Our study revealed that peripheral immunization, unlike inflammatory triggers, is essential to initiate an immune response against a liver antigen. We showed that liver T cell reactivity after peripheral immunization is marked by PD-1 and TIGIT co-expression and that the frequency of PD-1+ TIGIT+ HLA-DR+ CD38+ CD8 T cells in the blood of AIH patients is associated with liver injury. Our findings suggest a potential influence of the peripheral immunization for the liver-antigen-specific responses during AIH. Liver tissue-activated T cells probably recirculate during active phase of the disease, unveiling potential immunomarkers to monitor disease activity. HighlightsO_LIPeripheral immunization rather than local inflammation induces an immune response against a hepatic antigen C_LIO_LIPD-1 and TIGIT co-expression by T cells is found after tissue antigen-specific T cell reactivity C_LIO_LIFrequency of circulating PD-1+ TIGIT+ HLA-DR+ CD38+ CD8 T cells is associated with AIH disease activity C_LI In briefGuinebretiere et al. demonstrate that after peripheral immunization, liver-antigen-specific T cell accumulation in the tissue is marked by local PD-1/TIGIT co-expression, a phenotype shared with liver and circulating T cell subsets enriched in active autoimmune hepatitis (AIH) patients. These findings suggest the influence of peripheral immunization on the initiation of AIH and provide potential immunomarker of AIH activity.

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Guinebretiere, T., Cardon, A., Judor, J.-P., Gavlovsky, P.-J., Roux, F., Huchet, V., Chevalier, C., Khaldi, M., Bardou-Jacquet, E., Elkrief, L., Lannes, A., Silvain, C., Schnee, M., Tanne, F., Lemoinne, S., De Martin, E., Vavasseur, F., Nicot, A., Brouard, S., Mosnier, J.-F., Gournay, J., Conchon, S., Renand, A.. 2025-09-02. Accumulation of PD-1+ TIGIT+ T cells in the liver after local antigen reactivity and during autoimmune hepatitis. https://doi.org/10.1101/2025.08.29.672936

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