NK cell receptor biology
A major focus of the laboratory has been to understand the molecular mechanisms that regulate NK cell activation with a particular focus on receptor/ligand interactions that regulate anti-viral immunity. Recognition of virus-infected or tumor cells by NK cells is dependent upon the signals received from an array of activating and inhibitory receptors including the killer cell immunoglobulin-like receptors (KIR), Ly49 and the CD94-NKG2 receptors, all of which recognise distinct types of MHC class I molecules. We have used molecular and structural approaches to show how CD94-NKG2A binds HLA-E (Immunity 27:900-11, Journal of Experimental Medicine 205:725-35) and more recently by analysing viral sequences obtained from the blood of bone marrow transplant recipients, shown how human cytomegalovirus can manipulate this interaction to modulate NK cell activation (Journal of Biological Chemistry 288:8679-90).
Figure 1: Recruitment of HLA-B57 (green) to the NK cell (red)/target cell interface.
We have a growing program of work focussed on the biology of KIR, NK cell receptors that recognise distinct groups of HLA-I molecules. While the ligands for some KIR are not clearly defined, there is increasing genetic evidence that individual KIR or KIR/HLA combinations are associated with disease progression in HIV-infected individuals, the outcomes following bone marrow transplantation for the treatment of leukemia, and even reproduction where specific KIR/HLA interactions are linked to preeclampsia. Nevertheless the molecular basis for these clinical associations remains unclear.
To better understand the reasons that the expression of the polymorphic KIR3DL1 and its ligands are associated with reduced viral loads in HIV-infected individuals, together with our collaborators at Monash University, we determined the structure of KIR3DL1 in complex with HLA-B57 (Nature 479:401-5). This study showed the function of the characteristic D0 domain, which is also a feature of a number of other KIR and also surprisingly showed that the majority of polymorphisms map to regions outside the HLA binding site. Our current work using both functional and structural approaches is focussed on determining how KIR polymorphisms impact both ligand binding and NK cell activation and how this can be related to the role of NK cells in viral infection, transplantation and reproduction.
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