T-cell Multiomic Analysis Identifies Subsets and Mechanisms of Interaction with Epithelial Cells in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and respiratory failure, with a median survival of 3–5 years. While T-cell numbers are elevated in IPF lungs, their contributions to fibrosis beyond inflammation remain poorly understood. Here, we performed multiplex imaging and single-cell RNA and protein profiling on ∼90,000 CD3⁺ T-cells from control and fibrotic lungs, revealing eleven distinct subsets of CD4⁺ and CD8⁺ T-cells. Among these, we identified a rare CD56⁺ regulatory T-cell subset that is highly activated in fibrosis and exhibits a sustained immunosuppressive phenotype. CXCR4/MIF signaling emerged as a central axis mediating T-cell–epithelial interactions, while epidermal growth factor receptor (EGFR) and TGFβ pathways dominated in multiple T-cell subsets. Our findings demonstrate that T-cells in IPF adopt nonclassical activation patterns, driven by epithelial interactions and the fibrotic microenvironment. These studies provide a foundation for exploring novel therapeutic strategies in IPF lungs by modulating T-cell behavior and communication networks.