Fine-tuning of adaptive immunity: Signalling in experienced T cells

T cells are a two-edged sword, in that the same activation mechanisms, which promote health, can also cause disease. Many patients word wide suffer from chronic autoimmune diseases or cancer where inappropriate or deficient activation of T cells play a major role. Developing improved therapies targeting experienced T cells are therefore a key challenge both nationally and internationally. In this project, we aim to elucidate how experienced T cells are controlled through their inner workings. We will take an unbiased approach, using novel state of the art techniques. We will combine gene editing of T cells with large-scale analysis of the resulting intracellular protein machinery in the edited T cells. This will allow us to delineate novel details in how experienced T cells are controlled through their intracellular machinery. This new information may allow design of improved immunotherapy against cancer or autoimmune diseases. So far in the project we have established methods and reagents that are necessary for the project, and we have started to collect data.

T cells are a two-edged sword, in that the same activation mechanisms which promote health can also cause disease. Many patients word wide suffer from chronic autoimmune diseases or cancer where inappropriate or deficient activation of T cells play a major role. Developing improved therapies targeting experienced T cells are therefore a key challenge both nationally and internationally. Ideally, experienced T cells should be manipulated based on their specificity, so that T cells with a given specificity are inhibited or promoted. However, the specificity of the autoreactive T cells is often not known. An alternative strategy is thus to target T cells via their intracellular signaling machinery. In this project, we aim to elucidate how experienced T cells are controlled through intracellular signaling. Our working hypothesis is that the normal function of experienced T cells relies on signals dependent on Lck-TSAd interactions. TSAd is an Lck adapter molecule that is specifically upregulated in experienced T cells. We will therefore examine signaling in T cells harbouring mutations in either Lck or TSAd and explore how this affect signaling in experienced T cells. We will take an unbiased approach, using novel, state of the art techniques. We will combine genomic editing of T cells with affinity based mass spectrometry analysis. This will allow us to identify signaling pathways in experienced T cells that are dependent on the Lck-TSAd interaction. The project will provide new information on how experienced T cells are activated and controlled. This may allow design of improved immunotherapy against cancer or autoimmune disease. As part of the project, we will use the information gained to start to test new modes for modulating signaling in experienced T cells.