T-cells are key orchestrators of airways inflammation, but the relative roles of different human T-cell subsets remain unclear. The aim of my PhD was to carry out a detailed investigation of T cell phenotypes in asthma in relation to severity and virus-induced exacerbations, with particular focus on interleukin-17 and TH 17 cells, and the recently described mucosal associated invariant T (MAlT) cells, to improve characterisation of severe asthma versus milder forms of asthma. A role for interleukin-17 secreting TH17 cells in asthma has been suggested by several groups. I used clinical and physiologic phenotyping to compare T-cell subsets in health and a spectrum of different asthma severities. Samples obtained via sputum induction, phlebotomy, and bronchoscopy were phenotyped using 9-colour flow-cytometry/sorting, RT-qPCR and multiplex ELlSA. The results of my thesis confirm the pre-eminence of TH2 cells in asthma and provide further evidence of a deficiency of bronchoalveolar Treg in severe asthma, as well as new evidence of a role for CD8+ Tc2 cells in eosinophilic disease. Conversely, the data do not indicate a significant role for TH17 or yo-17 cells in asthma. Mucosal immunity is intrinsically linked to the associated commensal or pathogenic microbes. In an exploratory study of these interactions I employed deep-sequencing to characterise the whole microbial and viral metagenome of the airways in asthma and health. MAlT cells are novel innate-like T-cells which express an invariant TCRa chain and recognise the highly-conserved restriction molecule MR1. I observed a selective deficiency of MAlT cells in asthma, which was not related to age, but exacerbated by systemic corticosteroids and subject to seasonal variation, indicating their possible regulation by vitamin D. I established MAlT cell-lines and observed heterogeneity of cytokine expression profiles. These findings open exciting new avenues for research in this emerging area of T cell biology.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588885 |
| Date | January 2013 |
| Creators | Hinks, Timothy S. C. |
| Contributors | Djukanovic, Ratko ; Gadola, Stephan D. |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://eprints.soton.ac.uk/360451/ |
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