Identification and characterisation of the eukaryotic lipotoxicity interaction network (LIN) and modifiers of diacylglycerol-acyltransferase (DGAT)-mediated diseases

There is an ongoing need to understand the molecular mechanisms responsible for generating protective immunity to aid rational vaccine design. Various vaccine administration sites contain unique distributions of resident immune populations and other influencing factors in the microenvironment that may alter adaptive immune response generation. Typically, vaccination is administered intramuscularly or subcutaneously, however, many infectious diseases invade their hosts through the mucosal membranes, including the respiratory tract. Thereby, administering vaccines through the mucosa may represent a more natural infection route and establish specialised immune responses.To date, the importance of vaccine administration site remains unclear and thus should be investigated to understand whether specific local vaccination sites are of relevance in achieving desired immune responses.

The main goal of vaccination is to activate antigen-presenting cells (APCs), such as dendritic cells (DCs), to then prime the adaptive immune response. DCs lie at the interface between innate and adaptive immunity, thus, to take up antigen they patrol body sites commonly invaded by pathogens, such as the skin and lung. Upon antigen uptake, DCs migrate to the draining lymph node to interact with T cells, resulting in CD4+ T cell activation and differentiation into distinct T helper subsets. Due to their remarkable ability to sense their environment and interact with pathogens, the context of DC activation instructs the adaptive immune response to react in the manner most suitable to eliminate the particular pathogen. Therefore, DCs are central to gaining a better understanding of the events involved in initiating an immune response.

The aim of this investigation was to compare the immune cell composition and response in the skin and lung microenvironments. To address this, I used the novel vaccine adjuvant, αGalCer, which specifically activates innate-like natural killer T (NKT) cells and DCs, leading to peptide-specific T cell responses. APC activation and adaptive immune response generation were assessed in the skin and lung. I discovered that there was a greater proportion of T cells specialised to help B cells in the skin, compared to an enriched effector T cell phenotype in the lung. Additionally, the lung immune response was found to depend specifically on DC1 subset activation and the cytokine IFN-γ, likely produced by NKT cells upon activation, thus providing a mechanism for differential immune response generation in the skin and lung. These findings indicated that the tissue microenvironment could influence the adaptive immune response generated by vaccination, which is of great importance in the context of vaccine design.