Molecular mechanisms underlying T cell subset imbalance and precision therapeutic targets in primary biliary...

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by progressive destruction of small intrahepatic bile ducts and cholestasis-associated hepatic fibrosis. Although ursodeoxycholic acid and second-line agents improve biochemical indices in many patients, approximately 10%-20% still progress to cirrhosis or require liver transplantation. This therapeutic gap reflects the bidirectional, self-amplifying interplay between intrahepatic cholestasis and immune dysregulation, while the core immunopathological mechanisms remain incompletely defined and single-effector cell-centered models are insufficient to explain bile duct-targeted injury. Within this context, T cell subset imbalance has emerged as a key conceptual framework for precision intervention. This review synthesizes current evidence on T cell subset imbalance in PBC and posits that T cell heterogeneity and network dysregulation constitute both a central pathogenic basis and a rational therapeutic target. Specifically, imbalance of the Th17/Treg ratio among CD4⁺ T cells, clonal expansion of bile duct-specific CD8⁺ T cells, and quantitative and functional abnormalities of unconventional T cell subsets - including γδ T cells, double-negative T cells, mucosal-associated invariant T cells, and invariant natural killer T cells - are closely associated with disease activity, cholangitis severity, and fibrosis progression. This review discusses how the Th17/Treg axis, cytotoxic CD8⁺ T cells, and γδ T cells interact in the pathogenesis of biliary epithelial cell injury, inflammatory microenvironment remodeling, and the vicious cycle between impaired mitophagy and immune activation. Moreover, this paper summarizes current progress and unresolved issues related to putative or emerging targeted therapeutic strategies in PBC, including IL-17 pathway inhibition, CD8⁺ T-cell-directed approaches, γδ T-cell modulation, and combination immunotherapy, most of which remain preclinical or indirectly supported in PBC. In conclusion, we present perspectives of future directions for precision immunotherapy in PBC with a focus on major gaps in knowledge such as those that exist between animal models and human disease, the impact of tissue-resident memory T cells in the longer term, and how single-cell multi-omics and spatial omics can accelerate mechanistic insights and translate these more rapidly into the clinic.