Production and role of IL-17 and related cytokines in response to respiratory pathogens.
PhD thesis, University of Glasgow.
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Background: Pneumonia is a disease of the lungs that is caused by a number of pathogens including Gram-negative Pseudomonas aeruginosa and Gram-positive Streptococcus pneumoniae. These pathogens are prevalent causes of hospital-acquired pneumonia, and P. aeruginosa is particularly problematic with regards to chronic pulmonary infection in patients with Cystic Fibrosis (CF). Antibodies are known to provide a component of host-defence against this microbe, but recent evidence suggests that cells secreting the pro-inflammatory cytokine interleukin-17 (IL-17), namely T helper 17 (Th17) cells, are also significant in these responses.
Aim: To investigate the sources of IL-17 and related cytokines during P. aeruginosa and S. pneumoniae infection, and to investigate if IL-1β has a role in Th17 formation during infection with these pathogens. Furthermore, to investigate the cytokine secretion of dendritic cells (DCs) derived from different sources following infection with these pathogens, and their roles at inducing Th17 secretion from naive CD4+ T cells.
Methods & Results: Dendritic cells from mucosal sites were found to be better than GM-CSF derived bone marrow dendritic cells (BMDCs) at inducing Th17 cells from naive T cells. Th17 cells were derived in response to both P. aeruginosa and S. pneumoniae, with the role of IL-1β seeming to be negligible for P. aeruginosa. However, the role of IL-1β during Th17 cell induction during S. pneumoniae is unclear and needs further investigation. γδ T cells were found to be a source of IL-17 during P. aeruginosa infection in a IL-23 dependent manner. Furthermore, γδ T cells were also found to be a source of IL-22, yet the majority of cells were either IL-17 or IL-22 producing, not double producers as expected. In vivo infection with these pathogens identifed γδ T cells to be a main source of IL-17 during P. aeruginosa infection, with Th17 cells having more of a role during S. pneumoniae infection, yet the main sources of IL-17 still need to be identified. Preliminary infections with S. pneumoniae in IL-17RKO mice identified IL-17 as a key mediator in downstream inflammatory responses in the lung during infection.
Conclusions: This study demonstrates that IL-17 responses are induced in response to infection with the respiratory pathogens P. aeruginosa and S. pneumoniae. Ex vivo, mucosal DCs were found to induce more robust Th17 cell responses compared to GM-CSF derived BMDCS. In vivo, Th17 cells appear to have a role in S. pneumoniae infection, with γδ T cells appearing to be the dominant source of IL-17 during P. aeruginosa infection. Furthermore, in vitro investigations of γδ T cells found them to be differentially IL-17 and IL-22 producing in response to P. aeruginosa infection, in a DC contact independent manner.
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