Natural killer cells in the airways: Do they matter?
Authors: J. Lundahl, M. Hansson
Journal: Allergy (2003)

Natural killer (NK) cells are T-cell receptor-negative, large granular lymphocytes that comprise 5–15% of peripheral blood lymphocytes, and have been implicated in innate immunity against viruses, intracellular bacteria, and parasites. They exert their action by cytolytic activity and by cytokine production, for example, γ-interferon (IFN). In contrast to resting T-lymphocytes, NK cells express receptors for numerous cytokines and chemokines and produce γ-IFN and other NK–cell-derived cytokines/chemokines rapidly in response to activation. Their propensity to produce γ-IFN early in the immune response has given them a potential role in directing the nature of the subsequent acquired antigen-specific T-cell response. NK cells are normally present in the human lung, and several lines of evidence give them a potential role in pulmonary immunity, as well as in allergic asthma. Depletion of NK cells before immunization inhibited pulmonary infiltration of eosinophils and T cells in bronchoalveolar lavage (BAL) in a murine model of allergic asthma (1). An increased number of NK cells in BAL and lung parenchyma was reported in ovalbumin-sensitized and -challenged rats (2), and γ-IFN potentiated the effects of IL−13-induced lung injury, which was linked to higher levels of NK cells (3). Moreover, IL-5 producing NK cells promote allergen-induced allergic inflammation (4). Studies in humans have revealed that asthmatics have higher relative and absolute numbers of NK cells (5), and increased NK-cell cytotoxicity (6,7) that is further increased after allergen challenge (8). In contrast, Chou et al. (9) reported no significant difference between asthmatic children and healthy controls in numbers of NK cells, or their cytotoxicity and γ-IFN production. In addition, a reduced proportion of NK cells was assessed in the sputum of asthmatics (10). Recruitment of inflammatory cells constitutes a key event in the inflammatory response and the combined use of adhesion molecules and chemokines regulates the selection of cells entering the inflammatory lesion, thereby characterizing the cellular profile of a given inflammation. The earliest step in the process of recruitment begins when circulating cells marginate and start rolling on the endothelium. Adhesion molecules involved in this step are now believed to be the selectin family (L-, P- and E-selectins) and their carbohydrate-containing ligands. Subsequent to the selectin-dependent interaction, the process of firm adhesion and transendothelial migration starts; the responsible adhesion molecules are termed integrins and their Ig gene superfamily of ligands. Studies have revealed that NK cells depend on L-selectin for the rolling process, and that the nature of the interaction is regulated through quantitative expression of the receptor. For the subsequent adhesion and transmigration process, the leukocyte function associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1 adhesion pathway, and the very late activation antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1 adhesion pathway are both crucial determinants of the interaction with the vascular endothelium (11–13). Besides being a ligand for LFA-1, ICAM-1 is involved in the activation of T cells where this pathway functions as a coactivation signal. The ICAM-1 molecule is expressed on human NK cells and IL-2 exposure up-regulates the receptor and increases the lymphokine activated killer (LAK) cell activity. This increase in LAK activity is partially inhibited by anti-ICAM-1, which suggest that ICAM-1 contributes to the regulation of NK cytolysis (14). Attention has also been paid to ICAM-1 as an adhesion molecule involved in cell influx and as a receptor for rhinovirus. There is evidence that decreased γ-IFN production in vitro by peripheral mononuclear cells collected from infants during virus-induced bronchiolitis is associated with development of asthma (15). Reduced production of γ-IFN by NK cells may also play a role in the process of postviral chronic airway dysfunction (16). Thus, NK cells are likely to be an important source of γ-IFN during the innate host response to viral infections. This issue of Allergy features a paper by Lin et al. (22) that describes the expression of L-selectin and ICAM-1 on peripheral NK cells and T cells in children with allergic asthma with acute exacerbation, in a stable condition after treatment with oral steroids. The main finding of the study is an increased proportion of NK cells with decreased expression of L-selectin and ICAM-1 in asthmatic children with acute exacerbation compared to children in a stable condition. This finding can be attributed to selective recruitment of NK cells that are ICAM-1/L-selectin-positive into tissues, or an expansion of those that are ICAM-1/L-selectin negative. Some potential confounding factors must be taken into account. Virus infection is a recognized activator of NK cells and the common cold induces nasal influx of NK cells in both allergic and nonallergic people (17,18). An oral prednisolone course might per se have an impact on different NK cell phenotypes and cytotoxicity (7). Additional relevant control groups (e.g. children with virus infections without asthma) are warranted in future studies to strengthen a proposed causal relationship between NK-cell adhesion phenotype and asthma severity. However, their hypothesis is intriguing, namely that recruited NK cells are preferentially ICAM-1/L-selectin positive. One might speculate that L-selectin-positive NK cells are more prone to be recruited and when combined with ICAM-1 positivity, this might have impact on the action of NK cells in the tissue. NK cells that express ICAM-1 might favor ICAM-1-dependent actions of NK cells, such as cytotoxicity. This aspect might have bearing on the immune response since it was recently shown that macrophages and dendritic cells are vulnerable for NK-cell-mediated cytotoxicity, thereby modulating antigen presentation (19). Moreover, the action of histamine on NK cell function has recently gained attention, providing a potential link between a key factor in allergic asthma and NK cells. Histamine interferes with ICAM-1/LFA-1-dependent cytokine production in monocyte/NK-cell and T-cell cocultures (20) and protects NK cells against apoptosis induced by oxygen radicals (21). Although a significant role for NK cells in asthma has yet to be confirmed, the data presented by Lin et al. in this issue of Allergy support previous studies in the field that give NK cells a role in asthma pathogenesis in humans. However, several questions must be addressed about the potential mechanisms responsible for the proposed effect of NK cells before we can establish a role for NK cells. Prevention of NK-cell influx might be one therapeutic strategy to arrest the proposed harmful effects of NK cells in the airways, but to prevent unwanted effects one needs to appreciate the role of NK cells in innate immunity.