Translational Insights into T Cell Dysfunction and Precision Therapy in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by irreversible fibrosis and a gradual decline in pulmonary function. Its pathogenesis involves persistent epithelial injury, aberrant tissue repair, and excessive fibrotic remodelling driven by dysregulated immune responses. Growing evidence indicates that both innate and adaptive immune cells play a central role in disease progression. Despite advances in understanding its mechanisms, current treatments— pirfenidone, nintedanib, and nerandomilast—remain limited in efficacy. This study aimed to delineate the immunological landscape of IPF, characterize systemic T-cell dysfunction, and explore immune alterations in CD8⁺ cells following exposure to anti–PD-1 and nintedanib. Peripheral blood mononuclear cells (PBMC) from 47 IPF patients and 8 healthy controls were analysed by multicolour flow cytometry to assess the expression of the inhibitory receptors PD-1 and TIGIT on CD4⁺, CD8⁺, and CD56⁺ lymphocyte subsets. Purified CD8⁺ T cells from 5 IPF patients and 4 healthy controls were further stimulated in vitro and treated with anti–PD-1, nintedanib, or their combination to evaluate changes in activation, proliferation, and cytotoxicity. IPF patients exhibited a consistent upregulation and co-expression of PD-1 and TIGIT across CD4⁺, CD8⁺, and CD56⁺ T-cell subsets, indicating a state of systemic immune exhaustion. In vitro, CD8⁺ T cells showed dysregulated activation markers (CD25, CD69) and reduced cytotoxic potential (granzyme B, perforin). Neither anti–PD-1 nor nintedanib treatment restored functional competence and both maintained elevated inhibitory receptor expression, although nintedanib modestly enhanced CD8⁺ T-cell proliferation. Combined treatment did not reverse the exhausted phenotype, suggesting persistent overlapping inhibitory mechanisms and a stable imprint of chronic dysfunction. Overall, this PhD work reveals a marked systemic immune imbalance in IPF, characterized by persistent activation, inhibitory receptor overexpression, and functional exhaustion of T cells. The resistance of this phenotype to immunomodulatory interventions underscores the complexity of immune dysregulation in IPF and the need for therapeutic strategies targeting multiple inhibitory pathways.