Assessing the role of PKD family members for T cell function

Our research focus on molecular pathways regulating the function of T lymphocytes, which are important mediators of adoptive immune responses. This is of particular importance, since inappropriate or uncontrolled activation of T lymphocytes can lead to the development of diseases such as autoimmunity. On the other hand, harnessing T lymphocyte responses against cancerous cells is desirable. For instance, serinehreonine kinases, which are essential for the signal propagation down-stream of the T cell receptor complex, are potential targets for modulating T lymphocyte responses. Among others, members of the protein kinase D (PKD) family have been implicated in TCR signaling events. However, their exact function is currently unknown. Therefore, our proposal is set up to investigate the role of PKDs for T cell-mediated immunity. By elucidating the role of PKD-mediated signaling in T cells, we expect to significantly contribute to the understanding of signaling pathways regulating T cell activation. Additionally, we hope to identify novel targets within the PKD-signaling axis, which allows the modulation of T cell-mediated immune responses.

Assessing the role of PKD family members for T cell function T lymphocytes control whether our immune system fights pathogens, recognizes tumor cells, or attacks our own body by mistake. These decisions are triggered and processed by signals within the cell. Protein kinases, which are enzymes that pass on signals through phosphorylation, play a central role in this process. One such kinase is protein kinase D (PKD). In this project, we aimed to understand the role of PKD3 in particular in T cells and whether this kinase could be used to specifically enhance or slow down T cell-mediated immune reactions. Using genetic mouse models, we specifically switched off or permanently activated PKD3 in T cells and investigated its importance for activation and development in this immune cell type. Additionally, we developed an in vivo mixed lymphocyte reaction model to realistically measure polyclonal T cell responses. However, our results refuted our initial hypothesis that PKD3 is a master switch of T cell activation. Our findings demonstrate that PKD3 is not essential for fundamental T cell activation, as key activation features remained largely unchanged in mouse models lacking PKD3 in T cells. Conversely, permanently activating PKD3 in T cells did not lead to general overactivation. Rather, PKD3 acts as a fine regulator that influences the formation of memory T cells. These results have been published in peer-reviewed journals and help dispel the notion of PKD3 as a master switch.