Abstract
BackgroundThere is mounting evidence that perforin and granzymes are important mediators in the lung destruction seen in COPD. We investigated the characteristics of the three main perforin and granzyme containing peripheral cells, namely CD8+ T lymphocytes, natural killer (NK; CD56+CD3-) cells and NKT-like (CD56+CD3+) cells.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated and cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD8+ T lymphocytes, NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells were used in an LDH release assay to determine cytotoxicity and cytotoxic mechanisms were investigated by blocking perforin and granzyme B with relevant antibodies.ResultsThe proportion of peripheral blood NKT-like (CD56+CD3+) cells in smokers with COPD (COPD subjects) was significantly lower (0.6%) than in healthy smokers (smokers) (2.8%, p < 0.001) and non-smoking healthy participants (HNS) (3.3%, p < 0.001). NK (CD56+CD3-) cells from COPD subjects were significantly less cytotoxic than in smokers (16.8% vs 51.9% specific lysis, p < 0.001) as were NKT-like (CD56+CD3+) cells (16.7% vs 52.4% specific lysis, p < 0.001). Both cell types had lower proportions expressing both perforin and granzyme B. Blocking the action of perforin and granzyme B reduced the cytotoxic activity of NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells from smokers and HNS.ConclusionIn this study, we show that the relative numbers of peripheral blood NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells in COPD subjects are reduced and that their cytotoxic effector function is defective.
Highlights
There is mounting evidence that perforin and granzymes are important mediators in the lung destruction seen in Chronic obstructive pulmonary disease (COPD)
These conflicting findings may be due to the limits of some of the techniques employed and it is conceivable that other cell subpopulations expressing CD8 were included, i.e., CD8+ natural killer (NK) cells (CD3-CD8+CD56+CD16+/-) and natural killer T (NK-T) cells (CD3+CD8+CD56+)
CD8+ T cells can be divided into three subtypes, namely memory, naïve and the highly cytotoxic effector memory cells (TEMRA), the latter of which is determined by their high perforin content [18]
Summary
Chronic obstructive pulmonary disease (COPD) is a disease state characterised by progressive airflow limitation that is not fully reversible [1] It is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking [2]. It is known that lymphocytes can readily traffic between inflammatory sites (including lungs), regional lymph nodes, and importantly the systemic circulation, where they can be sampled [15] and may provide information using minimally invasive routes. This could be a benefit for subsequent biological and clinical investigations. To date no analysis has looked at the proportions of these subtypes
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