The role of iNKT cells on the phenotypes of allergic airways in a mouse model

Abstract

iNKT cells and mast cells have both been implicated in the syndrome of allergic asthma through their activation-induced release of Th2 type cytokines and secretion of histamine and other mediators, respectively, which can promote airways hyperresponsiveness (AHR) to agents such as methacholine. However, a mechanistic link between iNKT cells and mast cell recruitment or activation has never been explored. Our objective was to determine whether iNKT cells are necessary for the recruitment of mast cells and if iNKT cells can influence the acute allergen induced bronchoconstriction (AIB) caused by mast cell mediator release. To do so, we pharmacologically eliminated iNKT cells using a specific antibody (NKT-14) and examined its impact on airway inflammation and physiological phenotype. In mice treated with NKT-14, the elimination of iNKT cells was sufficient to prevent AHR and pulmonary eosinophilic inflammation elicited by administration of the iNKT cell agonist, αGalCer. In mice treated with NKT-14 and then sensitized and challenged with house dust mite extract (HDM), eliminating the iNKT cells significantly reduced both AHR and AIB but did not affect pulmonary inflammation, the mast cell population, nor the release of the mast cell mediators mast cell protease-1 and prostaglandin D2. We conclude that while iNKT cells contribute to the phenotype of allergic airways disease through the manifestation of AIB and AHR, their presence is not required for mast cell recruitment and activation, or to generate the characteristic inflammatory response subsequent to allergen challenge.

NKT cells contribute to basal IL-4 production but are not required to induce experimental asthma

“…This may overestimate the ratio of positive to negative data, because of the bias against publishing negative results. Importantly, results did not correlate with mouse strain used (usually BALB/c or C57BL/6); this makes it unlikely that subtle genetic drift could explain the striking differences found in these studies [ 85 , 98 ]. Consistent with this, our negative results were obtained with CD1d-deficient mice from the same commercial vendor (Jackson) that supplied the mice used in many of the positive studies.…”

“…To provide perspective regarding these conclusions, we extensively reviewed publications that investigated the role of the NKT cell in allergic airway disease and asthma. The essential information and conclusions from each paper that relate to NKT cell participation in allergic airway disease and asthma are shown in S2 Fig for mouse studies [ 27 – 37 , 68 – 98 ] and in S3 Fig 3 for human and non-human primate studies [ 38 – 41 , 99 – 108 ].…”

“…Of 42 mouse studies reviewed, 23 used α-gal-cer or another agent known to target NKT cells to influence the development of airway disease. Although the results of these experiments may be relevant to asthma pathogenesis, they do not directly address whether predominantly protein allergens act through NKT cells to induce disease [ 32 , 33 , 35 , 68 , 69 , 71 – 73 , 77 , 78 , 81 , 83 , 84 , 87 , 88 , 90 – 96 , 98 ]. Additional studies stimulated mice with purified cytokines and/or other non-protein pro-inflammatory agents, such as ozone [ 79 , 80 , 82 , 91 ].…”

Role of CD1d- and MR1-Restricted T Cells in Asthma

“…Although it is obvious that the direct activation of lung iNKT cells causes lung inflammation, which types of inflammation are induced is still controversial. Two groups claimed that the intranasal administration of α-GalCer induced allergic airway inflammation because eosinophil infiltration into the lung, a feature of type 2-mediated responses, was observed in IL-4- and IL-13-dependent manners ( 42 , 70 , 71 ). However, neutrophil infiltration, which represents non-allergic airway inflammation, is frequently observed in severe or Th17-mediated asthma ( 72 , 73 ).…”

“…Mouse invariant monoclonal antibody, NKT14 was found to specifically bind to invariant TCR of mouse iNKT cells and deplete iNKT cells in mice via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity for 3 weeks ( 80 ). The elimination of iNKT cells was sufficient to prevent murine AHR and pulmonary eosinophilic inflammation elicited by the oropharyngeal inhalation with α-GalCer ( 71 ). In addition, NKT14 administration prior to sensitization abrogated either antigen-mediated AHR alone or both AHR and pulmonary inflammation ( 71 , 80 ).…”