Project ID CM-HD2024_58


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

The role of the actin cytoskeleton in cytotoxic T cells for anti-tumour immunity

Our group is interested in the understanding the signalling pathways that control the migration of cytotoxic T cells (CTLs) into tumour tissues and the subsequent killing of the cancer cells. We do this by a combination of in vitro biochemistry and cell biology approaches, including CRISPR knockouts, advanced microscopy techniques and in vivo mouse model approaches. Our lab has recently identified the kinase WNK1 as a novel and important regulator of T cell killing and actin dynamics. In the absence of WNK1, CTLs fail to migrate into tumours and do not properly rearrange their actin cytoskeleton upon binding to a target cell. As a consequence, they are strongly defective in killing.

In this project the student will use primary mouse T cells to study the role of WNK1 in controlling TCR induced actin remodelling. During the first year research will focus on imaging actin dynamics during T cell killing in vitro through advanced microscopy techniques to further characterize the phenotype. From the second year onwards, the student will use biochemistry approaches to investigate the molecular basis of WNK1-signalling, concentrating on pathways that control actin polymerization and acto-myosin contractility based on preliminary data from lab. This will be done through immuno-blotting experiments, CRISPR-knockouts and overexpression studies to identify WNK1-dependent pathways and from year three onwards through pull downs, interaction studies and phosphoproteomics approaches to identify how WNK1 activates those pathways.

The work will be carried out in the Köchl lab in collaboration with Andrew Cope’s lab, a leading expert in studying T cell function and cancer biology.

Representative Publications

WNK1 kinase balances T cell adhesion versus migration in vivo. Köchl R, Thelen F, Vanes L, Brazão TF, Fountain K, Xie J, Huang CL, Lyck R, Stein JV, Tybulewicz VL. Nat Immunol. 2016 Sep;17(9):1075-83 and T cell migration requires ion and water influx to regulate actin polymerization. De Boer L, Melgrati S, Vanes L, Biggs O’May J, Hayward D, Köchl R, Tybulewicz VL. In revision at Nature Comms. bioRxiv 2022.03.16.484584; doi:
Super-resolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated adhesion with autoimmunity. Burn GL, Cornish GH, Potrzebowska K, Samuelsson M, Griffie J, Minoughan S, Yates M, Ashdown G, Pernodet N, Morrison VL, Sanchez-Blanco C, Purvis H, Clarke F, Brownlie RJ, Vyse TJ, Zamoyska R, Owen DM, Svensson LM, Cope AP. Sci Signaling 2016; 9: ra99.