Our lab is interested in cellular immunity and the interplay between cell surface receptors that drive the function of these cells. A focus of the lab is Natural Killer (NK) cells that keep constant watch over the body and detect and directly kill cells that have been transformed by viral infection or malignancy (cancer). Without NK cells, viral and tumour burdens are higher and progress more quickly.
We make use of protein chemistry, protein engineering and structural biology techniques to unravel the mechanisms of receptor/ligand specificity and how this regulates NK cell fate and function. Our goal is to improve the clinical application of NK cells to:
- understand susceptibility to disease and
- develop the next generation of immune-based therapies.
Current research projects
Variation in KIR receptors on NK can be exploited to improve bone marrow transplantation
The matching of donor bone marrow in haematopoietic stem cell transplantation (HSCT) is of critical importance to long-term successful treatment of a number of blood cancers, including acute myeloid leukaemia. Despite a growing appreciation that the mis-matching of donor KIR and recipient HLA can improve outcomes in HSCT, the field has nonetheless been hampered by a lack of data on allelic variation of KIR receptors. Our research aims to understand the biological consequences of KIR/HLA pairings such that high-resolution typing of KIR/HLA from donors and recipients can be used to improve long-term survival rates in HSCT.Natural Killer cells integrate inhibitory and activating signals
Harnessing NK cells is of benefit to a number of potential biotechnology applications. B-cell- and T-cell-based technologies have grown exponentially directly from basic research into understanding the role receptor molecules play in immune activation. These investigations have yielded chimeric-antigen T-cells, checkpoint inhibitors and antibody therapies. By comparison, NK cells show similar promise as platform technologies. Yet NK cell technology development lags that of T cells and B cells due to the complexity of the array of inhibitory and activating receptors that combine to drive functional diversity of NK cells. We aim to understand how inhibitory and activating signals are integrated to unlock new avenues for NK-based applications.
James Roest, Research Assistant
Moradi, S, Stankovic, S, O’Connor, G., Pymm, P, MacLachlan, BJ, Faoro, C, Retière, C, Sullivan, LC, Saunders, PM, Widjaja, J, Cox-Livingstone, S, Rossjohn, J#., Brooks, AG#, Vivian, JP#. Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C. Nature Communications. 12, 2173 (2021). DOI: 10.1038/s41467-021-22359-x
Saunders PM*, MacLachlan BJ*, Pymm P, Illing PT, Deng Y, Wong SC, Oates CVL, Purcell AW, Rossjohn J, Vivian JP#, Brooks AG# The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function Proceedings of the National Academy of Sciences (2020) 117 (21) 11636-11647. DOI: 10.1073/pnas.1920570117
Illing PT, Pymm P, Croft NP, Hilton HG, Jojic V, Han AS, Mendoza JL, Mifsud NA, Dudek NL, McCluskey J, Parham P, Rossjohn J, Vivian JP#, Purcell AW#. HLA-B57 micropolymorphism defines the sequence and conformational breadth of the immunopeptidome. Nature Communications. 2018 Nov 8;9 (1):4693. DOI: 10.1038/s41467-018-07109-w
Pymm P, Illing P, Ramarathinam S, Hughes VA, Hitchen C, O’Connor GM, Price DA, McVicar DW, Brooks AG, Rossjohn J#, Purcell A#, Vivian JP#. MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nature Structural and Molecular Biology. (2017) 24:387-394. DOI: 10.1038/nsmb.3381
Saunders PM, Pymm P, Pietra G, Hughes VA, Hitchen C, O’Connor GM, Loiacono F, Widjaja J, Price DA, Falco M, Mingari MC, Moretta L, McVicar DW, Rossjohn J#, Brooks AG#, Vivian JP#. Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition, Journal of Experimental Medicine. 2016 213: 791-807. DOI: 10.1084/jem.20152023
ORCID profile: 0000-0002-9400-4437
Google Scholar profile: https://scholar.google.com.au/citations?hl=en&user=r39A40EAAAAJ