"Human primary immunodeficiencies affecting cytotoxic lymphocyte function are associated with high morbidity and mortality. They often present as hyperinflammatory syndromes triggered by viral infections, hematological malignancies, or systemic autoimmunity. Although recent advances have provided molecular diagnoses for some of the most severe cases, only a handful of genes have been identified and disease in a majority of patients cannot be explained by current insights. My work has elucidated fundamental mechanisms of lymphocyte cytotoxicity. Furthermore, my group is leading international efforts in developing sensitive assays of human lymphocyte cytotoxicity. Some of our assays have been implemented for clinical diagnostics world-wide. Recently, we have also identified new, widespread mutations that explain many cases of fatal immunodeficiencies early in life. We now seek support for taking such studies to yet a higher level. The outlined interdisciplinary approach presented here aims at evaluating cytotoxic lymphocyte development and function in large numbers of patients, in addition to healthy individuals in a complementary approach, using state-of-the-art methodology. We will employ next-generation sequencing to identify novel genes associated with disease. The significance of putative mutations for lymphocyte cytotoxicity will be assessed using cutting-edge experimental platforms. Together, such genotype-immunotype studies promise to reveal novel genes associated with disease and further provide understanding of human genetic diversity. Thus, these studies can directly benefit patients through improved diagnosis, aiding targeted treatments, and offer new insights into human cytotoxic lymphocyte development and function with relevance to health. Insights will also pave the way for prospective, population-based molecular epidemiology studies required to more accurately assess the panorama of diseases associated with congenital defects in lymphocyte cytotoxicity."