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 to 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 and epithelial interactions, while epidermal growth factor receptor (EGFR) and TGF beta 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.