Natural killer cells in infection and cancer
Our overarching goal is to improve the clinical application of natural killer cells in order to: (1) understand susceptibility to disease and (2) to develop the next generation of immune-based therapies.
KIR receptors regulate NK function
Natural killer (NK) cells are cytotoxic cells that surveille the body and detect and kill cells that have been transformed by viral infection or malignancy. Depletion studies where NK cells have been deliberately removed have repeatedly shown higher and faster progressing viral and tumour burdens. Considered part of the innate immune system, NK cells nonetheless resemble other effector lymphocytes, the cytotoxic T cells and related B cells. However, NK cells differ in one crucial aspect. NK cells do not express antigen receptors encoded by genes that undergo recombination-activating gene-dependent recombination (for example the abT cell receptor (TCR)). Instead, NK cell fate, cytotoxicity and cytokine activity are determined by a complex interplay between numerous germ-line encoded receptors. Indeed, NK cells generate diversity through expression of a number of germ-line encoded receptors in a stochastic and clonal manner to produce thousands of distinct NK cell types per individual.
This raises a fundamental problem. How do thousands of distinct NK cell types scan the myriad of tissues in the body and not cause autoimmune reactions yet respond rapidly to viral or cancerous changes to cells? To do this, NK cells utilise a common pathway centred on the expression of Killer cell Immunoglobulin-like receptors (KIRs) that bind the ubiquitously expressed molecule Human Leukocyte Antigen class I (HLA). Though still not entirely understood, it is this KIR/HLA axis that acts as a “master regulator” of NK function and is key to utilising NK cells in the clinic for the treatment and prevention of numerous diseases including autoimmune diseases, viral infections and cancers.
The matching of donor bone marrow in haematopoietic stem cell transplantation (HSCT) is of critical importance to successful engraftment and long-term success for the treatment of a number of haematological malignancies including acute myeloid leukaemia. Great strides have been made in this area for HLA matching, with allele level HLA typing now routine. However, the contribution of ancillary factors has lagged. This is apparent for KIR receptors. 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 paucity of data on the effect of allelic variation within KIR receptors. Indeed, while it is accepted that HLA are the most highly variable (polymorphic) genes in the human genome, it is less appreciated that the KIR are extremely variability as well (1000s of variants), making KIRs the second most polymorphic gene cluster. Accordingly, the landscape of KIR/HLA interactions is vast. Previous attempts to consolidate KIR/HLA interactions have proposed “shortcuts” such as grouping KIR by “high” or “low” expression and typing by gene presence or absence. However, we have shown that these simplifications do not recapitulate the biological consequences of KIR/HLA pairings.
Central Hypothesis: That high-resolution typing of KIR, HLA from donors and recipients in HSCT treatment of AML will correlate with transplantation outcomes and long-term survival rates.
Understanding and harnessing the biology of NK cells is of significance and benefit to a number of potential biotechnology applications. Over the last decade, adaptive B cell and T cell based technologies have witnessed exponential growth that has arisen directly from basic research into understanding the role that T cell and B cell receptors and co-stimulatory molecules play in immune activation. These investigations have yielded chimeric-antigen T-cells (CAR-T-cells), T cell checkpoint inhibitor-based technologies and antibody therapies. These novel immunotherapies are the fastest growing area of the biotechnology sector globally. By comparison, innate immunity and NK cells show similar promise as platform technologies. Yet NK cells remain the least understood effector cell of the immune system. NK cells have proven quite intractable to study due to the complexity of the array of inhibitory and activating receptors that combine to drive diversity and function of NK cells. Understanding how these signals are integrated will unlock new avenues for biotechnology applications.
Note: #refers to joint senior authors.