Pro‐inflammatory role of natural killer cells in the development of allergic airway disease

Abstract

Background Natural Killer (NK) cells have been implicated in the development of allergic airway inflammation. However the in vivo role of NK cells has not been firmly established due to the lack of animal models with selective deficiencies in NK cells. Objective To determine the specific contribution of NK cells in a murine model of allergic airway disease (AAD). Methods The role of NK cells in AAD was studied using NK-deficient (NKD) mice, perforin−/− mice, and mice depleted of Ly49A/D/G+ NK cell subsets in an ovalbumin-induced model of allergic airway disease (OVA-AAD). Results Induction of OVA-AAD in C57BL/6 wild-type (WT) mice resulted in the expansion of airway NK cells and the development of pronounced airway eosinophilia. In the absence of NK cells or specific subsets of NK cells, either in NKD mice, or after the depletion of Ly49A/D/G+ NK cells, the development of OVA-AAD was significantly impaired as seen by decreased airway inflammation and eosinophilia, decreased secretion of the Th2 cytokines IL-4, IL-5 and IL-13 and diminished OVA-specific antibody production. Furthermore, while OVA-exposure induced a dramatic expansion of dendritic cells (DCs) in WT mice, their induction was significantly attenuated in NKD mice. Development of OVA-AAD in perforin−/− mice suggested that the proinflammatory role of NK cells is not dependent on perforin-mediated cytotoxicity. Lastly, induction of allergic disease by OVA-specific CD4 T cells from WT but not NK-depleted or NKD mice in RAG−/− recipients, demonstrates that NK cells are essential for T cell priming. Conclusions and Clinical Relevance Our data demonstrate that conventional NK cells play an important and distinct role in the development of AAD. The presence of activated NK cells has been noted in patients with asthma. Understanding the mechanisms by which NK cells regulate allergic disease is therefore an important component of treatment approaches.

PGI2 Controls Pulmonary NK Cells That Prevent Airway Sensitization to House Dust Mite Allergen

“…Previous reports studying the impact of NK cells on the development of allergic lung inflammation have yielded contradictory findings. In certain instances, NK cells inhibited allergic lung inflammation (14, 15) and in others they promoted eosinophilic inflammation (16, 53) reviewed in (54). In some studies, the antigen sensitization phase was more susceptible to NK cell-mediated regulation compared to the subsequent lung inflammatory response elicited by OVA inhalation (55).…”

NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice

“…In addition, emerging evidence has also revealed that NK cells can contribute to the immunopathogenesis of allergic airway disease by producing type 2 cytokines [11,15]. The depletion of NK cells decreased the secretion of IL-4, IL-5 and IL-13 and airway inflammation in an OVA-induced asthma mouse model [17]. Moreover, NK cells from asthmatic patients produced higher IL-4 than those from the healthy individuals [18].…”

“…In animal models, increased NK cells are observed in the lung following antigen challenge and depletion of the cells before immunization inhibits allergic airway inflammation [16]. In NK-deficient (NKD) mice, the development of OVAinduced model of allergic airway disease was significantly impaired as seen by decreased airway inflammation and eosinophilia, decreased secretion of the Th2 cytokines IL-4, IL-5 and IL-13 and diminished OVA-specific antibody production [17]. Moreover, in patients with asthma, NK cells are also dramatically increased and their phenotype is altered and may contribute to the promotion of a pro-inflammatory Th2-type environment [18].…”

Natural killer cells in asthma

“…Using the ovalbumin (OVA)-induced model of asthma Korsgren et al and Mathias et al showed that depletion of NK cells either prior to immunization (depleting antibodies) or throughout the life of an animal (genetically-modified mice) prevents production of IL-4 in lymphoid organs, generation of ovalbumin-specific IgE, infiltration of lungs by eosinophils and T cells and production of pulmonary type-2 cytokines [6, 7]. Thus, NK cells are likely necessary for differentiation of naïve T cells into Th2 cells and initiation of adaptive type-2 responses.…”

“…Thus, NK cells are likely necessary for differentiation of naïve T cells into Th2 cells and initiation of adaptive type-2 responses. Mathias and colleagues investigated importance of NK cells in T cell priming in an adoptive transfer model [7]. CD4+ T cells from sensitized NK cell-deficient mice were unable to induce eosinophilia in lungs of allergen-challenged RAG1−/− recipients, while CD4+ T cells from WT recipients were fully capable to do so.…”