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

T-celler er et to-egget sverd. Aktivering av disse cellene kan fremme helse, men samme type celle-aktivering kan også være årsak til sykdom. Verden over er det mange pasienter som lider av kroniske autoimmune sykdommer eller kreft, hvor upassende eller manglende aktivering av T-celler spiller en avgjørende rolle. Utvikling av bedre behandlinger som retter seg mot erfarne T-celler er derfor en nøkkel-utfordring både i Norge og internasjonalt. Målet med dette prosjektet er å undersøke hvordan det indre maskineriet i erfarne T-celler kontrollerer disse cellene. Vi vil bruke moderne teknologier for å angripe problemstillingen på en bredest mulig måte. Vi vil kombinere genredigering i T-celler med storskalert analyse av det intracellulære protein-maskineriet i disse endrete T-cellene. Slik kan vi avsløre nye detaljer i hvordan erfarne T-celler blir aktivert og kontrollert. Denne typen informasjon kan gi grunnlag for utvikling av bedre immunterapi mot kreft eller autoimmune sykdommer. Til nå i prosjektet har vi etablert metoder og reagenser som er nødvendig for prosjektet, og vi har begynt å samle inn 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.