Controlling immunity at dendritic cell and T cell level by host, pathogens, and as therapeutics

A balance between immune activation and inhibition is essential to attack and eliminate pathogens whilst protecting against harmful effects on the host. To prevent ineffective or excessive immune responses, activation of dendritic cells (DCs) and T cells is controlled at different levels. Here, we have investigated how the host as well as pathogens affect immune responses by DCs and T cells and whether we can use this knowledge for therapeutic purposes. In this thesis, in part I we have studied how sensing of SARS-CoV-2 by DCs is influenced by viral mediators as well as host factors. In addition, we identified a mechanism by which SARS-CoV-2 suppresses immune responses, enhancing susceptibility to bacterial superinfections. We also explored the therapeutic potential of DCs and developed a method to harness sensing mechanisms to induce strong T cell responses against tumors. In part II we described the design and optimization of methods to successfully genetically modify primary murine and human T cells to efficiently knockdown, knockout, or overexpress genes of interest. Subsequently we have used this toolbox to study the functional role of several genes during T cell activation and T cell receptor (TCR) downregulation in primary human T cells. Collectively, these results show that DC and T cell activation is controlled at multiple levels, not only by host factors but also by pathogens. By unraveling the mechanisms used by pathogens as well as the host to influence immune cell activation, we might find ways to target these mechanisms for the generation of efficient immunotherapies