Peptide-Specific Natural Killer Cell Receptors in Health and Disease

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Cells of the immune system must differentiate friend from foe. They achieve this by using cell surface protein machines called receptors that can 'see' signs of infection or cancers. When receptors 'see' their targets, immune cells spring into action, and some will kill the target cells and alert other cells to the site of danger by producing molecular messages. Different immune cells use different combinations of receptors to detect their targets. Developing new medicines to treat infections and cancer requires understanding how immune cells and their receptors detect their targets. One mechanism the immune system uses to detect their targets is called the 'HLA antigen presentation pathway'. HLA proteins are specialized molecules found on almost all cells that have the unique ability to capture small fragments (peptides) from inside the cell and place them on the cell surface. During infections and cancer, those peptides have different amino acid sequences to those not normally found on healthy cells can be 'seen' by immune cells using their specialized receptors. For many years, we've known that immune cells called T cells are very good at detecting these HLA presented peptides and use a special peptide detecting receptor called the T cell receptor (TCR). Recently, my research and others have shown that receptors expressed on a different immune cell, natural killer (NK) cells, also detect these peptides. However, in contrast to TCRs, very little is known about these peptide-specific natural killer cell receptors (PSNKR). The goal of this project is to develop a comprehensive understanding of how PSNKRs contribute to immunity. Natural killer (NK) cells are specialized immune cells with the capacity to kill infected cells and tumours. The PSNKRs include receptors called NKG2C, NKp44 and some members of the killer-cell immunoglobulin-like receptors (KIR) family. The first goal of the project will be to define PSNKR using novel screening technologies. I have expertise in studying KIR and recently developed screens to define KIR peptide-specificity of KIR, while the specificities of NKG2C and NKp44 will be defined through collaborations. The data from these screens will feed algorithms that can predict whether any HLA presented peptide will bind PSNKRs or not. The peptides presented by HLA proteins are called the 'immunopeptidome' and the identity (amino acid sequence) of these peptides differs between cells types and in disease conditions. The identity of these peptides under different diseases are unknown. Through collaborations, immunopeptidomes will be defined from cells implicated in multiple human diseases including HIV infection, cancer and pre-eclampsia (a disorder of pregnancy). These peptides will then be tested for PSNKR binding, facilitated by prediction algorithms, and then tested their ability to activate NK cells. After identifying functional PSNKR ligands, methods to manipulate immunopeptidomes to increase the frequency of PSNKR binding peptides will be deployed. One method will develop a new technology called Antibody-peptide epitope conjugates (APEC). APECs can deliver peptides to the cell surface of HLA proteins and activate T cells, redirecting them towards tumours. I will develop APECs to target PSNKRs, a potentially novel medicine that can redirect NK cells towards target cells. NK cells express many different receptors in addition to PSNKRs. My final goal will be to investigate how NK cells integrate signals from PSNKRs and other activating receptors. NK cell activation will be controlled by carefully dosing HLA proteins in the presence of proteins that bind other NK cell receptors. This will help model how PSNKRs respond to target cells in different disease contexts. Together this research program will provide molecular insight into a poorly understood receptor family and their role in multiple human diseases, facilitating development of novel molecular medicines.