Doherty Institute - Theses
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ItemInvestigating the interactions between dendritic cells, T cells and B cells mediated by targeting Clec9A( 2016)Dendritic cells (DC) are endowed with an array of receptors that can be exploited for immunotherapy. Targeted delivery of antigen to CD8α+ DCs via Clec9A in vivo induces versatile immune responses, most notably potent thymus-dependent humoral responses even in the absence of adjuvant. However, the basis of the immunogenicity of Clec9A-targeted antigen remains incompletely understood. This thesis describes the complex interactions between CD8α+ DCs and T and B cells mediated by Clec9A to promote and/or regulate immunity. Characterization of CD4+ T cells responding to Clec9A-targeted antigens revealed that they had the phenotype, localization pattern and effector functions consistent with T follicular helper cells (TFH) that provide B cell help. Furthermore, targeting Clec9A primed long-lived memory CD4+ T cells capable of robust secondary TFH responses, even in the absence of adjuvant. Thus, in the steady-state Clec9A-targeted CD8α+ dendritic cells are capable of stimulating CD4+ T cells to promote the development of fully polarized TFH cells. Strikingly, Clec9A was also found to mediate direct interactions between CD8α+ DCs and B cells. B cells were rapidly activated through recognition of native antigen presented on the surface of CD8α+ DCs upon Clec9A-targeted immunization. Direct activation of B cells by CD8α+ DCs was critical for optimal Clec9A-mediated antibody responses as it enabled B cells to effectively acquire help from cognate CD4+ T cells at the T/B borders within the spleen and lymph nodes. Thus, the effective triad of interactions mediated by Clec9A drives potent antibody responses in the steady-state. Unlike TFH and B cells that were potently activated in the steady-state, cross-priming of cytotoxic lymphocytes (CTLs) by Clec9A-targeted antigen required co-administration of adjuvant. In contrast to B cells, Clec9A-mediated primary CTL responses were impaired by the presence of CD4+ T cells. Clec9A-mediated MHC II-restricted presentation favoured the expansion of pre-existing Foxp3+ regulatory T cells (Tregs) in the steady-state, which presumably impaired non-Tregs capacity to activate CD8α+ DCs. Collectively, the data presented in this thesis reveal the versatile capacity of CD8α+ DCs to interact with various cell types to promote immunity/tolerance and reinforces the notion that targeting Clec9A in vivo is a promising strategy to exploit for immunotherapy.