Genome-wide dissection of Human NK cell Development and Disease Networks

Natural killer (NK) cells are critical innate immune effectors providing a first line of defence against viral infection and malignant transformation. Despite decades of study, the genetic architecture governing NK cell development, maturation and function remains poorly characterised — a fundamental gap with direct consequences for patients with immunodeficiencies, for NK cell therapeutic strategies, and for understanding infection and cancer susceptibility. A central barrier has been the challenge to genetically manipulate NK cells. Methodological advances I have developed make efficient, high-viability CRISPR editing of NK cells feasible, enabling genome-wide functional screening in these cells for the first time. Building on this, two interconnected aims will be pursued. Aim 1 will combine a deeply characterised human ex vivo NK cell differentiation system with genome-wide CRISPR loss-of-function screens, generating a comprehensive catalogue of genetic requirements for NK cell development, maturation and function. Aim 2 will directly link discoveries to human disease through an immunodeficiency patient cohort, construct regulatory networks from single-cell CRISPR screens, with further linkage through GWAS loci for relevant traits. Together, these aims will deliver the first genome-wide functional map of human NK cell biology, providing a diagnostic framework for immunodeficiency patients and a mechanistic basis for improving NK cell therapies.