The major impact of immunological pathways in the pathogenesis of human disease makes Immunology a key discipline in the Department of Medicine, with PIs distributed across several Institutes on the Biomedical campus. Our vision is to understand the molecular mechanisms underlying immune-mediated disease and use these insights to inform new diagnostic and therapeutic strategies. To this end we have established a unique partnership between basic and clinical scientists. Major themes include understanding how cytotoxic T lymphocytes (CTL) initiate and terminate the immune response, and how viruses and tumours evade them. The complexity of the T-cell signalling network is analysed using light-mediated control, allowing us to probe the molecular details of T-cell activation, and determine how lymphocytes avoid the anti-proliferative signals of inflammation and regulate anti-viral and anti-tumour immunity. Studies on how CTL engage their targets demonstrate how polarised secretion destroys virus-infected and tumour target cells. The aim is to understand how these specialised secretory lysosomes deliver their lethal hit at the immunological synapse and the molecular basis of this polarized secretion. Our genetic approaches use CRISPR/Cas9 genome-wide screens to determine how viruses evade immune detection. We also identified HUSH, a novel epigenetic repressor complex that assembles heterochromatin to silence newly-integrated retroviruses. HUSH represses HIV, as well as endogenous retrotransposons, offering new therapeutic opportunities. Our work is underpinned by superb infrastructural expertise and support in flow cytometry, proteomics and single cell analyses.