Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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.
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 exhausted phenotype, play a crucial role in liver damage, and are controlled by immune checkpoint pathways. Our findings thus suggest that circulating autoreactive CD4 T cells in AILD are imprinted by chronic antigen exposure to promote liver inflammation, thereby serving as a potential target for developing biomarkers and therapies for AILD.
Autoimmune liver diseases AILD are rare immune-mediated chronic inflammatory diseases. The three main AILD are autoimmune hepatitis AIH , primary biliary cholangitis PBC , and primary sclerosing cholangitis PSC , which are characterized by the destruction of the liver parenchyma, the intrahepatic biliary epithelial cells of small bile ducts or the intra- or extra-hepatic biliary epithelial cells of the large bile ducts, respectively. PSC is a more complex disease often associated with ulcerative colitis 8.
Although all three AILD are classified as autoimmune diseases, the degree of intensity of the autoreactive response appears to be variable, and the link with the autoimmune T-cell signature is unknown.
In AILD, the strong association with the HLA locus, the presence of autoantibodies in serum and of T cells in damaged tissue reflect the complete adaptive immune response against self-antigens, with a central role for CD4 T cells with their helper function 9 , 10 , 11 , However, it has been difficult to establish in-depth the immune profile of autoreactive CD4 T cells, as they are rare in the blood and not all self-antigens are known.
