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Title: The role of Natural Killer cells in allergic airway inflammation
Author: Farhadi, Nazanin
ISNI:       0000 0004 5918 0261
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Natural Killer (NK) cells are innate cells of the immune system and constitute 10% of lung lymphocytes. Increasing evidence implicates a role for innate immunity in the pathogenesis of asthma and although there is evidence of a role for NK cells in the development of allergic inflammation, the mechanisms by which NK cells contribute to allergy is not known. To characterise the NK cell response and determine the phenotype of NK cells in allergic pulmonary inflammation we employed a model in which mice are dosed intranasally 3 times a week for 3 weeks with house dust mite (HDM) extract. Numbers of NK cells in the bronchoalveolar lavage (BAL) increased over the time course of HDM challenge and followed a similar trend to eosinophils and Th2 cells. Airway NK cells were activated and expressed NKG2D and granzyme B. In addition, expression of the NKG2D ligand (MULT-1) was upregulated in the lungs of mice treated with HDM. To determine the importance of the NKG2D receptor in allergic inflammation, the HDM model was tested on NKG2D knock out (KO) mice. There was a dramatic reduction in the extent of the inflammatory response in the absence of this receptor, including a reduction in BAL eosinophilia, Th2 responses and serum IgE. Adoptive transfer of wild type (WT) NK cells into NKG2D KO mice restored allergic inflammatory responses to HDM, whereas transfer of granzyme B-/- NK cells did not, demonstrating the requirement for NK cell expression of NKG2D and granzyme B. Detailed phenotypic analysis of NKp46+ cells in the HDM model showed that NKp46+ cells in BAL and lung consisted of RORγt+ and RORγt- subsets. NKp46+RORγt- cells resembled conventional NK cells as they express NKG2D and granzyme B, however NKp46+RORγt+ had similar phenotype to type-3 innate lymphoid cells (ILC3) cells and produced Th2 cytokines upon HDM challenge. We have shown for the first time that NK cells promote allergic lung inflammation via NKG2D and granzyme B production. We have also described for the first time the presence of NKp46+RORγt+ cells in the airways and lung which identifies potential novel therapeutic targets.
Supervisor: Culley, Fiona Sponsor: Medical Research Council ; Asthma UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral