Transcriptomic, clonal, and functional analyses reveal Liver tissue-imprinted immuno-profile of circulating autoreactive CD4 T cells in autoimmune liver diseases

Cardon, A.; Guinebretiere, T.; Dong, C.; Gil, L.; Ado, S.; Gavlovsky, P.-j.; Braud, M.; Danger, R.; Schultheiss, C.; Domene, A.; Paul-Guilloteaux, P.; Chevalier, C.; Bernier, L.; Judor, J.-P.; Fourgeux, C.; Imbert, A.; Khaldi, M.; Bardou-Jacquet, E.; Elkrief, L.; Lannes, A.; Silvain, C.; Schnee, M.; Tanne, F.; Vavasseur, F.; Brusselle, L.; Brouard, S.; Kwok, W.; Mosnier, J.-F.; Lohse, A. W.; Poschmann, J.; Binder, M.; Gournay, J.; Conchon, S.; Milpied, P.; Renand, A.

doi:10.1101/2024.03.26.586770

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bioRxiv · 10.1101/2024.03.26.586770

Transcriptomic, clonal, and functional analyses reveal Liver tissue-imprinted immuno-profile of circulating autoreactive CD4 T cells in autoimmune liver diseases

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Abstract

Autoimmune liver diseases (AILD) are immune-mediated disorders in which CD4 T cells play a central role. However, the link between circulating self-antigen-specific CD4 T cells and the targeted tissue has not been extensively studied in AILD. We hypothesized that circulating autoreactive CD4 T cells were clonally and functionally related to dominant intra-hepatic pathogenic CD4 T cell clones. Single cell transcriptomic analysis of circulating self-antigen-specific CD4 T cells revealed a specific B-helper and immuno-exhausted transcriptional profile, which was conserved for different autoantigens, but distinct from several other types of foreign antigen specificities. In the blood, the dominant hepatic CD4 T cell clones had a similar transcriptomic signature and were enriched in the PD-1+ TIGIT+ HLA-DR+ CD4 T cell subset. In a mouse model, antigen-specific CD4 T cells acquired the immuno-exhausted transcriptional profile when they accumulated in the liver after local antigen reactivity. Locally, immune checkpoint molecules controlled the response of antigen-specific CD4 T cells responsible for liver damage. Our study reveals the origin and biology of liver-derived autoreactive CD4 T cells in the blood of AILD patients that are imprinted by the liver environment, and suggest a dysregulation of the immune checkpoint molecules pathways. Our study enables tracking and isolating circulating autoreactive CD4 T cells for future diagnostic and therapeutic purposes.

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Cardon, A., Guinebretiere, T., Dong, C., Gil, L., Ado, S., Gavlovsky, P.-j., Braud, M., Danger, R., Schultheiss, C., Domene, A., Paul-Guilloteaux, P., Chevalier, C., Bernier, L., Judor, J.-P., Fourgeux, C., Imbert, A., Khaldi, M., Bardou-Jacquet, E., Elkrief, L., Lannes, A., Silvain, C., Schnee, M., Tanne, F., Vavasseur, F., Brusselle, L., Brouard, S., Kwok, W., Mosnier, J.-F., Lohse, A. W., Poschmann, J., Binder, M., Gournay, J., Conchon, S., Milpied, P., Renand, A.. 2024-03-29. Transcriptomic, clonal, and functional analyses reveal Liver tissue-imprinted immuno-profile of circulating autoreactive CD4 T cells in autoimmune liver diseases. https://doi.org/10.1101/2024.03.26.586770

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