Hedgehog signalling in T cell effector and memory function in vivo. (360G-Wellcome-107609_Z_15_Z)

The aim of my research is to characterize the role of Hedgehog (Hh) signalling - known as a key determinant of tissue differentiation and development - in regulating CD8 effector and memory formation and function in vivo. I will utilize Hh reporter mice to determine the level of Hh signalling in effector and memory subsets during the course of the CD8 response to infection and tumour challenge. By comparing Hh-deficient and wildtype, antigen-specific CD8 T cells, I will interrogate the functiona l relevance and clinical importance of Hh signalling. RNASeq analysis on CD8 subsets and single cells will be carried out to reveal the Hh-specific CD8 target gene signature responsible for the observed effects in the different CD8 subsets. Novel Hh target genes identified in this analysis will be functionally characterized. In parallel I investigate the effects of Hh pathway manipulation on the CD8 anti-tumour response using live-imaging approaches of whole animals and tumour slices. The prop osed study will not only reveal the spatio-temporal activation and functional relevance of Hh signalling during the CD8 immune response in vivo but will also identify the underlying molecular mechanisms and determine the effects of Hh inhibitors and agonists on this response.