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T-regulatory cells and programmed death 1+ T cells contribute to effector T-cell dysfunction in patients with chronic obstructive pulmonary disease.

American journal of respiratory and critical care medicine (2014-05-16)
Suresh Gopi Kalathil, Amit Anand Lugade, Vandana Pradhan, Austin Miller, Ganapathi Iyer Parameswaran, Sanjay Sethi, Yasmin Thanavala
ABSTRACT

Previous studies from our laboratory have shown that peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) prone to exacerbations with nontypeable Haemophilus influenzae have impaired responses to lipoprotein P6. We hypothesized that an underlying immunosuppressive network could be responsible for the defective antibacterial immunity observed in these patients. We evaluated T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and exhausted T effector cells (programmed death 1 [PD-1](+)) in patients with COPD, because these cells are known to play a pivotal role in suppressing immune responses. We performed an in-depth characterization of Tregs, T effector cells, and MDSC in COPD and correlated their levels and function with disease severity. Treg, effector T cell, and MDSC frequency from patients with COPD and healthy subjects' PBMCs were analyzed by flow cytometry. Treg immunosuppressive capacity was measured by in vitro suppression assay. The frequency of interferon-γ producing T cells and T-cell proliferation were measured after blocking CTLA-4 and PD-1. Plasma proinflammatory and immunosuppressive cytokine levels were measured. Significantly increased levels of Tregs, MDSC, and PD-1(+) exhausted effector T cells were present in patients with COPD compared with healthy subjects. Tregs from patients with COPD suppressed P6-specific T-cell proliferation to a greater extent than Tregs from healthy subjects. Plasma levels of Treg-generated cytokines, IL-10, and transforming growth factor-β were elevated. Blockade of CTLA-4 resulted in significant augmentation of T-cell IFN-γ production in patients with COPD. Functionally suppressive Tregs, MDSCs, and exhausted PD-1(+) T cells contribute to effector T-cell dysfunction in COPD.

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