Epithelial CD155–TIGIT/CD226 signaling links CD8⁺ T-cell exhaustion to frequent exacerbations in COPD

BACKGROUND: The immune mechanisms underlying chronic obstructive pulmonary disease (COPD) remain incompletely understood, particularly regarding immune checkpoint dysregulation. This cross-sectional observational study aimed to determine whether activation of the T-cell immunoglobulin and ITIM domain (TIGIT) pathway contributes to CD8-positive T-cell exhaustion and susceptibility to frequent exacerbations in COPD. METHODS: We integrated publicly available single-cell RNA sequencing data from human lung tissue with analyses of peripheral blood, bronchoalveolar lavage fluid, and lung tissue obtained from patients with COPD and healthy controls. Flow cytometry was used to assess CD8-positive T-cell differentiation and expression of TIGIT and its co-stimulatory counterpart CD226, while immunohistochemistry quantified the TIGIT ligand CD155 in airway and alveolar epithelium. Functional assays, including cytokine production, apoptosis, and lentiviral TIGIT knockdown, were conducted to evaluate the reversibility of TIGIT-mediated exhaustion. RESULTS: Single-cell and flow-cytometric analyses revealed an expansion of terminally differentiated effector memory CD8-positive T cells re-expressing CD45RA with high TIGIT expression in COPD, particularly among frequent exacerbators. CD155 was upregulated in airway and alveolar epithelial cells, whereas CD226 expression on CD8-positive T cells was reduced. TIGIT-positive CD8-positive T cells exhibited decreased tumour necrosis factor-alpha and interferon-gamma production and increased apoptosis. TIGIT knockdown restored cytokine secretion and reduced apoptosis, indicating a reversible exhausted phenotype. CONCLUSION: The TIGIT-CD155/CD226 pathway is associated with epithelial stress, CD8⁺ T-cell exhaustion and frequent exacerbations in COPD. Targeting this immune checkpoint may help restore antiviral immunity and reduce airway damage, providing a promising therapeutic avenue for immune modulation in chronic airway disease.