Journal: Frontiers in Pharmacology

Article Title: Molecular mechanisms underlying T cell subset imbalance and precision therapeutic targets in primary biliary cholangitis

doi: 10.3389/fphar.2026.1769883

Figure Lengend Snippet: Schematic illustration of the vicious cycle underlying bile duct injury in PBC. This figure illustrates that immune disturbance, metabolism disorder and BEC damage form a self-reinforcing loop in PBC. Central to all these processes is imbalanced T cell subsets, characterized by a high Th17/Treg ratio that can be exacerbated by γδ T cells. Dendritic cells (DCs) and macrophages (Mφ) secrete IL-23, driving STAT3-dependent Th17 differentiation/expansion. γδ T cells also exert an upstream effect through the secretion of IL-21 that promotes Th17 polarization while promoting the instability of Tregs. IL-17A from Th17s affects BECs, which induces release of pro-inflammatory cytokines and chemokines that recruit immune-cells. BEC injury occurs mainly via CTLs using perforin-granzyme pathway, leading to the apoptosis of BEC and loss of bile ducts. This immune damage is amplified by another metabolic feedback loop: defective BEC mitophagy results in accumulation and secretion of mitochondrial DAMPs (e.g., PDC-E2), inducing the activation of innate immunity and promoting a Th17 response; while granzymes released from CTLs aggravate the mitochondrial injury in BECs. As a counter-regulatory mechanism, bile acid-activated FXR and Peroxisome proliferator-activated receptor γ (PPARγ) signaling converge to suppress NF-κB-dependent inflammatory transcription, reducing inflammation and promoting restoration of T cell subset balance. Although not depicted as a separate node in the central schematic, tissue-resident memory T cells (Trm) are discussed in as an additional mechanism contributing to chronicity, relapse, and long-term immune persistence in PBC. Abbreviations: BEC, biliary epithelial cell; CTLs, cytotoxic T lymphocytes; DAMPs, damage-associated molecular patterns; FXR, farnesoid X receptor; PPARγ, peroxisome proliferator-activated receptor γ; TGR5, Takesda G protein-coupled receptor 5; SASP, Senescent-associated secretory phenotype; Trm, tissue-resident memory T cells.

Article Snippet: These bile acids directly impair mitochondrial integrity, downregulate anion exchanger 2 expression, and reshape CD4 + T cell fate via signaling mediated by the FXR, Takeda G protein-coupled receptor 5 (TGR5), and the sphingosine-1-phosphate receptor-signal transducer and activator of transcription 3 (S1PR-STAT3) axis.

Techniques: Amplification, Activation Assay