Secretion at the immunological synapse. (360G-Wellcome-075880_Z_04_A)

The goal of this research is to identify and understand the mechanisms that regulate secretion from cytotoxic T lymphocytes (CTL). The secretory granules of CTL are unusual as they are also the lysosomes of these cells, and the mechanisms controlling their secretion differ from those of secretory granules in other cell types. The primary aim of this proposal is to use human genetic diseases in which CTL function is impaired to identify novel proteins required for secretion from CTL. We will complement this approach with use of lentiviral expression in CTL to identify additional proteins involved in secretion which might give rise to embryonic lethal mutations. We will combine molecular, biochemical, microscopical and immunological techniques to dissect the molecular interactions required for each step leading to secretion at the immunological synapse. Using these techniques we will determine the role of cytoskeletal proteins, exocyst and SNARE proteins in CTL secretion. We will also examine the later steps of CTL killing, characterising the microenvironment of the secretory cleft and the mechanisms that lead to membrane acquisition from target cells by CTL, asking whether this mechanism plays a role in regulating the CD8 response and in preventing hemophagocytosis