Elevated Th1 and terminally differentiated cytotoxic T cells with suppressed Tc17 lymphocytes in lung tissue of advanced COPD and IPF patients undergoing lung transplantation

Irena Šarc^1,2*Matthias Zimmermann^3,4Ana Koren⁵Matija Rijavec^6,7Hendrik Jan Leonard Ankersmit^3,8Peter Korosec^6,9

• ¹University Clinic of Pulmonary and Allergic Diseases Golnik, Golnik, Slovenia
• ²Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
• ³Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria
• ⁴Department of Oral and Maxillofacial Surgery, Medical University of Vienna, Vienna, Austria
• ⁵University Clinic of Respiratory and Allergic Diseases, Golnik, Golnik, Slovenia
• ⁶University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia
• ⁷Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
• ⁸Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
• ⁹Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

Introduction: The immunopathogenesis of end-stage chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) remains poorly understood. Emerging evidence suggests that distinct T cell subpopulations may play critical roles in the progression of both diseases. A better understanding of these roles could provide important insights into underlying mechanisms and guide the development of targeted therapies. Methods: We performed flow cytometric analysis of explanted lung tissue from patients with advanced COPD (n = 9), IPF (n = 9), and idiopathic pulmonary arterial hypertension (IPAH, n = 3) undergoing lung transplantation. Healthy donor lung tissue (n = 7) served as controls. Results: Both COPD and IPF lungs demonstrated an increased frequency of Th1 (CXCR3⁺CCR4-CCR6-) lymphocytes compared to controls. In contrast, Tc17 cells were significantly reduced. No notable differences were observed in Th2, Th17, or Tc1 cell populations. Activated CD4⁺ T cells (CD69⁺CD25⁺HLA-DR⁻/⁺) were significantly enriched in IPF com-pared to COPD and donor lungs. COPD lungs exhibited a marked expansion of terminally differentiated cytotoxic CD8⁺CD28⁻CD27⁻ T cells. In double-negative (DN; CD3⁺CD4⁻CD8⁻) T cell compartment, CD25⁺ T cells were increased in COPD, whereas DN tissue-resident memory (TRM; CD69+CD25-HLA-DR-) cells were reduced in both COPD and IPF. Invariant natural killer T (iNKT; Vα24⁺Vβ11⁺) cell levels were uniformly low without intergroup differ-ences. Discussion: Our findings identify disease-specific immune signatures in end-stage COPD and IPF. Th1 cell expansion together with a reduction in Tc17 and DN TRM subsets represented shared features of COPD and IPF, whereas accumulation of terminally differentiated cytotoxic CD8⁺ T cells and CD25⁺ DN T cells was specific to COPD. These findings enhance our understanding of adaptive immune dysregulation in COPD and IPF and may support the development of immunomodulatory strategies.