Multiomic analysis identifies T cell subsets and mechanisms of epithelial interaction in idiopathic pulmonary fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and respiratory failure. While T cells 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 about 90,000 CD3+ T cells from control and fibrotic lungs, revealing 11 distinct subsets of CD4+ and CD8+ T cells, including a rare CD56+ regulatory T cell. In addition to increased T cell numbers in severely fibrotic lungs compared with non-diseased controls, we observed CD4+ and CD8+ T cells localized near epithelial cells and in niches of abnormal epithelium. CXCR4/MIF signaling emerged as a central axis mediating T cell–epithelial interactions, while epidermal growth factor receptor (EGFR) and TGF-β pathways dominated in multiple T cell subsets. Our findings support the concept that T cells in IPF adopt nonclassical activation patterns that are driven by epithelial interactions within the fibrotic microenvironment. These studies provide a foundation for exploring alternative therapeutic strategies in IPF lungs by modulating T cell behavior and communication networks.

Authors

Ana P.M. Serezani, Julia M.R. Bazzano, Bruno D. Pascoalino, Ludmilla da Silva, Abigail J. Dietrich, Chase J. Taylor, Taylor Sherrill, Annika Vannan, Carla L. Calvi, Paula I. Gonzalez-Ericsson, Erin M. Wilfong, Matthew Bacchetta, Ciara M. Shaver, Lorraine B. Ware, Margaret L. Salisbury, Luc Van Kaer, Nicholas E. Banovich, Jonathan A. Kropski, Timothy S. Blackwell