Natural killer cells in the lung: novel insight and future challenge in the airway diseases

Abstract

Natural killer (NK) cells are innate lymphoid cells which are present in the lung as circulating and resident cells. They are key players both in airway surveillance and in crosstalk with (COPD) pathogenesis, and they seem to contribute to the development of bronchiectasis. In asthma, NK cell dysfunction was observed mainly in severe forms, and it can lead to a biased type-2 immune response and failure in the resolution of eosinophilic inflammation that characterise both allergic and eosinophilic phenotypes. Moreover, aberrant NK cell functions may interfere with antimicrobial immune response contributing to the frequency and severity of virus-induced exacerbations. In COPD, lung NK cells exhibit increased cytotoxicity against lung epithelium contributing to lung tissue destruction and emphysema. This cell destruction may be exacerbated by viral infections and cigarette smoke exposure through NKG2D-dependent detection of cellular stress. Lastly, in bronchiectasis, the airway NK cells might both promote neutrophil survival following stimulation by proinflammatory cytokines and promote neutrophil apoptosis. Systemic steroid treatment seemingly compromises NK activity, while biologic treatment with benralizumab could enhance NK cell proliferation, maturation and activation. This narrative review gives an overview of NK cells in airway diseases focusing on pathophysiological and clinical implications. Together, our findings emphasise the pleiotropic role of NK cells in airway diseases underscoring their possible implications as to therapeutical approaches.

FIGURE 1

Natural killer (NK) cell phenotype and distribution. Among all lymphocytes, the proportion of lung NK cells ranges from 5% to 20%. Of these cells, it is possible to distinguish the circulating NK cells and the resident NK cells. Most circulating NK cells belong to the mature CD56^dimCD16⁺ phenotype. In contrast, tissue-resident lung NK cells are mostly composed of CD56^brightCD16⁻ and are characterised by the expression of three markers: CD69, CD49a and CD103. IL: interleukin; TNF-α: tumour necrosis factor-α; IFN-γ: interferon-γ.

FIGURE 2

Proposed model of natural killer (NK) cells’ cytotoxic activity in asthma and COPD. In asthma, NK cells interact with airway eosinophils inducing the extrinsic pathway of apoptosis. Apoptosis is mainly carried out by Fas/FasL signalling and by the release of Granzyme B and perforin. NK-mediated eosinophil apoptosis leads to the resolution of airway inflammation. NK cytotoxicity against eosinophils is weakened by systemic steroid treatment and increased by the interaction between lipoxin A4 and ALX/FPR2 receptors. In COPD, the expression of MIC-A/B cellular stress by the lung epithelium, enhanced by smoke exposure, induces the activation status of natural killer cells through the binding to NKG2D. Lung-resident NK cells exhibit increased cytotoxicity against lung epithelial cells. NK cytotoxic responses contribute to lung tissue destruction and emphysema. NK cytotoxic responses are boosted by DC's IL-15 trans-presentation. IL-15: interleukin-15.

FIGURE 3

Graphical summary of the main functions of natural killer (NK) cells in the different airway diseases.