Killer-cell immunoglobulin-like receptors on the cusp of modern immunogenetics

Killer-cell immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) ligands play a central role in immunity and human health. These molecules are encoded by gene families with copy number variation, extreme levels of sequence diversity and complex expression patterns. The rapid evolution of KIR and HLA genes and their associations with infectious diseases, pregnancy disorders, immunopathologies and outcome of cell transplantation have generated considerable interest from immunologists, geneticists and clinicians. Until recently, however, analyses have been stuck at low-level resolution, focusing primarily on presence or absence of KIR genes. This is changing with the advent of modern high throughput sequencing, cell phenotyping and bioinformatics. These developments allow high-resolution analysis and much deeper understanding of KIR evolution and KIR function. The impending deluge of high dimensional data brings inevitably new challenges in analysis, interpretation and communication of results, but the benefits are already tangible. The diversity of KIR across worldwide human populations is being catalogued at the allele level. Structures of KIR molecules and their interactions with HLA-peptide complexes are being determined. How KIR modulate natural killer cell education is being defined. Ligands for activating KIR, elusive for many years, are being discovered. KIR gene complexes and their related receptor gene families are being characterized in animal models and livestock breeds. These advances are helping to generate a more complete picture of the impact of KIR variation in health and disease and offer new opportunities for immunotherapy, as highlighted in a recent meeting (The Tenth KIR Workshop, April 2017 Cambridge, UK).