Hedgehog signalling in CD8 Tcell memory differentiation

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Hedgehog (Hh) signalling plays an important role during embryonic development and adult tissue maintenance. In the immune system the Hh pathwayis involved in thymic T cell development. Until recently it was unclear whether the Hh pathway is active or required in mature T cells. Mature naïve CD8T cells in the periphery are not terminally differentiated. Upon pathogen or tumour challenge naïve T cells can develop into highly effective killer cells(Cytotoxic T Lymphocytes, CTL) and several long-lived memory subsets that self-renew and persist to protect the host upon re-challenge. Interestingly,the work of Dr. de la Roche showed that Hh signalling, initiated by the T cell receptor, is crucial for CTL killing (de la Roche et al, Science 2013).Whether Hh signalling also regulates CD8 memory cell formation, maintenance and functional capacity is unknown. The aim of this project is todetermine the functional relevance of Hh signalling in CD8 memory cells using in vivo reporter and conditional knockout mouse models. We aim tocomplement the in vivo systems with the use of tissue culture and genetic manipulation of primary lymphocytes combined with flow cytometry, basiccell biology and biochemistry techniques. Advances in elucidating the signalling pathways that guide memory formation and function will guidetherapeutic approaches to infection, cancer immunotherapy, and vaccine development.