Candida albicans is a human fungal pathogen responsible for superficial mucosal infections and life-threatening systemic disease. Despite the availability of potent antifungal drugs, mortality rates of systemic candidiasis remain high. Alternative therapies and vaccines are therefore desirable; however their generation depends on a comprehensive understanding of antifungal immunity. Innate recognition of fungi by the immune system is primarily mediated by a class of myeloid-expressed molecules termed the C-type lectin receptors (CLRs). CLRs mediate a variety of functions including phagocytosis, fungal killing, initiation of inflammation, and the generation of adaptive immunity. Adaptive responses are required for long-term memory and are shaped by the initial innate immune response controlled by CLR-expressing myeloid cells, yet the influence of CLRs on fungal-specific adaptive immunity is not well understood. In this thesis, the generation of C. albicans-specific T-cell immunity, particularly the CD4+ T-cell response, was investigated using OT.II transgenic T-cells and an ovalbumin-expressing strain of C. albicans. Using this model system, a novel role for the CLR, Dectin-1, was found in controlling CD4+ T-cell viability and recruitment to the GI tract. No roles for Dectin-1, or the related CLR Dectin-2, were found in controlling T-cell responses in the C. albicans infected kidney. However, it was found that, surprisingly, antigen-specific CD4+ T-cells did not migrate into the kidney during infection. Artificial restoration of this defect using immunoliposomes could significantly protect against infection, thus highlighting the importance of these lymphocytes to antifungal immunity. Furthermore, this thesis also explores the generation of better tools to study C. albicans-specific T-cell responses, and the roles of uncharacterised CLRs in the generation of adaptive immunity. Collectively, this research provides new insights into the generation and regulation of antigen-specific CD4+ T-cell immunity during C. albicans infections.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:619179 |
| Date | January 2014 |
| Creators | Drummond, Rebcca Anne |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=211412 |
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