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Lung CD8+ T cells in COPD have increased expression of bacterial TLRs

Christine M Freeman12*, Fernando J Martinez2, MeiLan K Han2, George R Washko,3, Alexandra L McCubbrey4, Stephen W Chensue457, Douglas A Arenberg2, Catherine A Meldrum2, Lisa McCloskey2 and Jeffrey L Curtis246

Author Affiliations

1 Research Service, Department of Veterans Affairs Healthcare System, Ann Arbor, MI 48105, USA

2 Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA

3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard University, Boston, MA, 02115, USA

4 Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA

5 Pathology & Laboratory Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA

6 Medical Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA

7 Department of Pathology, University of Michigan Health System, Ann Arbor, MI, 48109, USA

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Respiratory Research 2013, 14:13  doi:10.1186/1465-9921-14-13

Published: 1 February 2013

Abstract

Background

Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown.

Methods

Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants.

Results

All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-γ and TNF-α by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD.

Conclusions

These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1.

Keywords:
Chronic obstructive pulmonary disease; CD8+ T cells; Toll-like receptors; Lung