Microbiology & Immunology - Theses
Permanent URI for this collection
Search Results
1 - 2 of 2
-
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.
-
ItemCharacterization of roles of IRF8 in dendritic cell development and function( 2018)Dendritic cells (DC) are an essential component of immune system. Antigen presentation by DCs initiates T cell responses and builds up defense against pathogens. There are two major types of DC, conventional DCs (cDCs) and plasmacytoid DCs (pDCs), both of which derive from the same progenitor. The cDCs can be further classified by surface marker CD11b and CD8. While cDCs function as the major antigen presenting cells, pDCs are more efficient in type I IFN production. Regarding the functional difference, it is important to comprehend factors that control the production of these two types of DC. It has been reported that IRF8 mutation in human causes selective loss of DC subsets. Although IRF8 has been identified as key regulator in DC transcription network, study addressing the function of IRF8 in DC development and function remains incomplete. In this project, we show that the generation of pDCs and cDC1s depends largely but not entirely on IRF8. Upon germline deletion of IRF8, normal function of pDCs was disrupted while the antigen presentation of cDC1s was complemented by other mechanisms.