In the Voskoboinik laboratory, researchers investigate the regulation and function of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, which play a key role in the surveillance of virus-infected and cancer cells.
Cytotoxic lymphocytes recognise and kill cancerous and virus-infected cells through the cytotoxic granule exocytosis pathway. Cytotoxic granules store a pore-forming protein, perforin, and serine proteases, granzymes. Once released, perforin transiently disrupts a target cell membrane, thus permitting the delivery of granzymes into the cytosol, where they initiate various apoptotic death pathways. This is a fundamental homoeostatic process; when disrupted, it has catastrophic consequences: it leads either to fatal hyperinflammation, or in milder cases results in haematological malignancies in childhood or adolescence.
Clarifying the biology of CTL and NK cells is critical to help understand the fundamental principles of immunity, predisposition to paediatric blood cancers and immune deficiency. We take a multidisciplinary approach that encompasses immunology, biochemistry, structural biology, cell biology and genetics.
Regulation and function of cytotoxic lymphocytes
Cytotoxic lymphocytes recognise and kill cancerous and virus-infected cells through the cytotoxic granule exocytosis pathway. Cytotoxic granules store a pore-forming protein, perforin, and serine proteases, granzymes. Once released, perforin transiently disrupts a target cell membrane, thus permitting the delivery of granzymes into the cytosol, where they initiate various apoptotic death pathways. This is a fundamental homoeostatic process; when disrupted, it has catastrophic consequences: it either leads to fatal hyperinflammation, or in milder cases results in haematological malignancies in childhood or adolescence.
- The regulation of cytotoxic granule exocytosis
- The structural bases of perforin pore formation
- The biology of granzymes
- The molecular bases of congenital immune deficiency familial haemophagocytic lymphohistiocytosis
- The genetic predisposition to haematological malignancies.
Castiblanco D, Rudd-Schmidt JA, Noori T, Sutton VR, Hung YH, Flinsenberg TWH, Hodel AW, Young ND, Smith N, Bratkovic D, Peters H, Walterfang M, Trapani JA, Brennan AJ, Voskoboinik I. (2022). Severely impaired CTL killing is a feature of the neurological disorder Niemann-Pick disease type C1. Blood. 139(12):1833-1849.
Voskoboinik I, Lacaze P, Jang HS, Flinsenberg T, Fernando SL, Kerridge I, Riaz M, Sebra R, Thia K, Noori T, Schadt EE, McNeil JJ, Trapani JA. (2020). Prevalence and disease predisposition of p.A91V perforin in an aged population of European ancestry. Blood.135(8):582-584.
Flinsenberg TWH, Tromedjo CC, Hu N, Liu Y, Guo Y, Thia KYT, Noori T, Song X, Aw Yeang HX, Tantalo DG, Handunnetti S, Seymour JF, Roberts AW, Ritchie D, Koldej R, Neeson PJ, Wang L, Trapani JA, Tam CS, Voskoboinik I. (2020) Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma. Haematologica. 105(2):e76-e79.
Rudd-Schmidt, JA., Hodel, AW., Noori, T., Lopez, JA., Cho, HJ., Verschoor, S., Ciccone, A., Trapani, JA., Hoogenboom, BW., Voskoboinik, I. (2019). Lipid order and charge protect killer T cells from accidental death. Nat Commun 10, 5396.
Opat, S., Hearps, A.C., Thia, K., Yuen, H.L.A., Rogers, B., Chachage, M., Moore, G., Shortt, J., Ryland, G., Blombery, P., Schwarer, A.P., Noori, T., Trapani, J.A., Jaworowski, A. and Voskoboinik, I. (2018). Adaptive reprogramming of NK cells in X-linked lymphoproliferative syndrome. Blood. 131:699-702.
House, I.G., House, C.M., Brennan, A.J., Omer, G., Dawson, M.A., Whisstock, J.C., Law, R.H.P., Trapani, J.A. and Voskoboinik, I. (2017). Regulation of perforin activation and pre-synaptic toxicity through C-terminal glycosylation. EMBO Reports. 18:1775-1785.
Leung, C., Hodel, A.W., Brennan, A.J., Lukoyanova, N., Tran, S., House, C.M., Kondos, S.C., Whisstock, J.C., Dunstone, M.A., Trapani, J.A., Voskoboinik, I.*, Saibil, H.R.*, and
Hoogenboom, B.W.* (2017). Real-time visualization of perforin nanopore assembly. Nature Nanotech. 12:467-473. * equal senior author.
Voskoboinik I, Whisstock JC and Trapani JA (2015). Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 15: 388-400.
Jenkins MR, Rudd-Schmidt JA, Lopez JA, Ramsbottom K, Mannering SI, Andrews DM, Voskoboinik I* and Trapani JA* (2015). Failed CTL/NK cell killing and cytokine hyper-secretion are directly linked through prolonged synapse time. J Exp Med. 212: 307-317. (* equal senior authors)
Lopez JA, Susanto O, Jenkins MR, Lukoyanova N, Sutton VR, Law RHP, Johnston A, Bird CH, Bird PI, Whisstock JC, Trapani JA, Saibil HR and Voskoboinik I (2013). Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood. 121: 2659-2668.
Brennan AJ, Chia J, Browne KA, Ciccone A, Ellis S, Lopez JA, Susanto O, Verschoor S, Yagita H, Whisstock JC, Trapani JA and Voskoboinik I (2011). Protection from Endogenous Perforin: Glycans and the C-Terminus Regulate Exocytic Trafficking in Cytotoxic Lymphocytes. Immunity. 34: 879-892.
We offer projects in each of these areas, and a specific topic will be selected to cater for the interests and skills of a candidate. A prospective student will be a part of a successful multidisciplinary research team of immunologists, biochemists, cell biologists, geneticists and clinical scientists, and will gain experience in immunology, cell biology (including various microscopy techniques), molecular biology and biochemistry.