Microbiology & Immunology - Theses
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ItemDissecting the role of gd T cells in T cell priming for liver stage immunity( 2023-11)Liver resident memory T cells (TRM) are poised for protection against repeat infection and rapidly form a robust defence against tissue-specific insults such as liver stage malaria. A direct correlation between liver stage immunity and gd T cells has been observed both in mice (Zaidi et al. 2017) and in humans (Seder et al. 2013; Ishizuka et al. 2016), but the precise molecular mechanisms by which these gd T cells exert their protective effect are yet to be defined. In mice, intravenous injection with radiation-attenuated sporozoites (RAS) confers sterile protection against challenge with live sporozoites. This protection is mediated by responding antigen-specific CD8+ and CD4+ T cells that migrate to the liver and form resident-memory T cells (TRM). In the absence of gd T cells, protective CD8+ liver TRM are not generated, leaving mice susceptible to reinfection. Using Plasmodium-specific T cells as a readout for effective immunity, we determined that IL-4 is important for the accumulation of CD8+ and CD4+ T cells. By utilising complex in vivo systems including mixed-bone marrow chimeras and adoptive transfer of gd T cells, we revealed that gd T cell-derived IL-4 is crucial for the expansion of antigen-specific CD8+ T cells. In addition, in vivo neutralisation of IL-12 or IFN-g confirmed a partial dependency for these cytokines, despite their traditionally opposing function to IL-4. Given IL-4, IFN-g and IL-12 all have a clear role in CD8+ T cell priming following RAS vaccination, we hypothesised that IL-4 and IFN-g synergise to enhance cDC1 activity. These findings led to our development of a novel model to reconstitute cDC1-deficient mice using CRISPR-edited primary dendritic cells. This model enabled the investigation of the mechanism by which gd T cell derived IL-4 leads to DC activation and therefore effective CD8+ T cell expansion for memory development. Collectively, this project has shown a significant role for IL-4 in the priming of malaria-specific CD8+ T cells and demonstrates a novel pathway for collaboration between gd T cells, cDC1s, and CD8+ T cells, revealing the potential for harnessing gd T cells in vaccination strategies against malaria.
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ItemThe role of CD8+ tissue-resident memory T cells in melanoma immune surveillance.( 2018)In addition to its role in protecting the body from infection, the immune system can prevent the development of cancer in a process termed tumour immune surveillance. During this process, immune cells can either recognise and completely eliminate cancerous cells, or can suppress the outgrowth of malignant cells without completely eradicating them. This latter mode of control, designated ‘cancer-immune equilibrium’, can be sustained for extended periods of time in a manner dependent upon adaptive immune cells such as T cells. The vast majority of human cancers are spawned from epithelial tissues. However, long-lived CD8+ circulating memory T (TCIRC) cells such as effector memory T (TEM) cells and central memory T (TCM) cells are typically excluded from epithelial tissue compartments in the absence of robust inflammation. In contrast, CD8+ tissue-resident memory T (TRM) cells are a population of non-migratory immune cells that permanently occupy epithelial tissue sites without recirculating. CD8+ TRM cells provide efficacious protection against peripheral viral and bacterial infections and have recently been identified in a variety of human solid tumours, where they associate with improved disease outcome. However, a direct role for TRM cells in promoting natural immunity to cancer has yet to be demonstrated. In this thesis, we examined the contribution of CD8+ TRM cells to peripheral cancer immune surveillance and the mechanisms through which these cells protect against tumour progression. In order to study the peripherally localised anti-tumour immune response, we developed and characterised an orthotopic epicutaneous (e.c.) model of melanoma in mice that targets tumour growth to the outermost layers of skin. We found that a portion of mice receiving tumour cells e.c. remained free of macroscopic cancer long after inoculation, in a manner that depended upon immune cell mediated control. Spontaneous protection from progressive tumour development was associated with the formation of melanoma-specific CD69+CD103+ CD8+ skin TRM cells, whereas mice genetically deficient in TRM cell formation were highly susceptible to tumour growth. Importantly, tumour-specific skin TRM cells could protect against tumour development independently of TCIRC cells. Closer inspection of macroscopically tumour-free mice revealed that many harboured occult melanoma cells in their skin long after e.c. inoculation. These dormant melanoma cells were retained in the epidermis, where they were dynamically surveyed by tumour-primed CD8+ skin TRM cells. Ablation of skin TRM cells from macroscopically tumour-free mice that were initially protected from tumour development triggered late-stage tumour outgrowth, demonstrating that CD8+ TRM cells can suppress cancer progression by promoting a state of subclinical cancer-immune equilibrium. Further, our findings suggest that the cytokine tumour necrosis factor (TNF) may play a role in the induction and maintenance of this equilibrium state. Overall, we show that CD8+ TRM cells contribute to immune surveillance of peripherally localised cancers by upholding tumour-immune equilibrium. As such, our findings elucidate how cancers arising in epithelial compartments are subject to long-term and ongoing immune suppression. Collectively, our work provides critical insight and the impetus necessary to exploit CD8+ TRM cells as targets of cancer immunotherapies in order to improve solid cancer treatments in patients.