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Global Impairment of CD4⁺CD25⁺FOXP3⁺ Regulatory T Cells in Idiopathic Pulmonary Fibrosis

¹ Department of Hematology and ² Department of Pneumonology, Democritus University of Thrace Medical School, Alexandroupolis; and ³ Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece

Correspondence and requests for reprints should be addressed to Ioannis Kotsianidis, M.D., Ph.D., Department of Hematology, Democritus University of Thrace, Medical School Dragana, Alexandroupolis 68100, Greece. E-mail: ikotsian{at}med.duth.gr

Rationale: The implication of T cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is controversial. CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs) are pivotal in maintaining immune homeostasis, but their role in IPF pathophysiology has not yet been studied.

Objectives: To explore Treg dynamics and function in IPF.

Methods: Treg levels and dynamics were analyzed by flow cytometry in the peripheral blood (PB) and bronchoalveolar lavage (BAL) of 21 patients with IPF, 35 patients with lung diseases other than IPF (patients without IPF), 20 patients with collagen vascular diseases with pulmonary parenchymal involvement (CVD-IP), and 28 healthy volunteers. The suppression of autologous CD4⁺CD25^– cell-proliferative responses and cytokine release by magnetic bead–isolated Tregs was evaluated by proliferation assays and cytometric bead array. Correlations of Treg function and levels with lung function parameters were also performed.

Measurements and Main Results: In patients with IPF, both BAL and PB Tregs were reduced compared with those of healthy volunteers and patients without IPF, although not always significantly. Treg levels were not affected by the administration of low-dose prednisone in four nonresponding patients. The suppressor potential of BAL and PB Tregs was compromised in patients with IPF and patients with CVD-IP, compared with healthy volunteers and patients without IPF. Similarly, the Treg-induced suppression of helper T-cell type 1 and 2 cytokine secretion was impaired in the BAL of patients with IPF and patients with CVD-IP. Moreover, the defective function of BAL Tregs correlated highly with parameters of disease severity.

Conclusions: This study provides the first evidence of global Treg impairment in IPF that strongly correlates with disease severity, suggesting a role for Tregs in the fibrotic process.

Key Words: Tregs • idiopathic pulmonary fibrosis • bronchoalveolar lavage • pulmonary function tests

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The role of T lymphocytes in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is controversial, but there are currently no data concerning FOXP3+ regulatory T cells in IPF. What This Study Adds to the Field This study demonstrates that patients with IPF have significantly impaired Treg activity, analogous to that described in various autoimmune diseases, which is likely implicated in the fibrotic process.

 

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