biostudies-literatureCardon AAgence Nationale de la RechercheAgence Nationale de la Recherche (French National Research Agency)1161https://www.ebi.ac.uk/biostudies/studies/S-EPMC11779892biostudies-literatureUnknown16(1)Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhaustNature communicationsSingle cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.PMC11779892ANR-19-CE17-0024Brouard SChevalier CSchultheiß CKwok WWTanne FGil LGavlovsky PJConchon SFourgeux CGournay JImbert ABinder MCardon ALohse AWBraud MDong CPaul-Gilloteaux PMilpied PGuinebretiere TElkrief LPoschmann JVavasseur FRenand ADanger RMosnier JFLannes ABernier LJudor JPBardou-Jacquet EBrusselle LSilvain CAdo SSchnee MDomene AKhaldi MfalseSingle cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhaust2025-01-01T00:00:00Z2025 Jan2026-06-02T07:26:33.919Z2025-04-07T04:21:28.921ZS-EPMC117798923988081910.1038/s41467-025-56363-2