Deciphering the Functional Regulation of Human Natural Killer Cells

Natural killer (NK) cells represent key cellular components of the innate immune system. Challenging the notion that NK cells are short-lived lymphocytes with a static phenotype, a more complex picture is currently emerging suggesting that NK cells underg o discrete stages of differentiation, and tune their responsiveness in a dynamic fashion. NK cells are functionally regulated by an array of germ-line encoded receptors including the stochastically expressed killer cell immunoglobulin-like receptors (KIR s). The KIR genes occupy one of the most rapidly evolving regions in the human genome, reflecting their co-evolution with polymorphic HLA class I ligands and highlighting their central role in human health. The outlined research aims at understanding the mechanisms governing the formation of human NK cell repertoires and their functional tuning by KIR/HLA interactions. In an interdisciplinary effort, molecular studies of human NK cell repertoires at the single cell level will be combined with an integrati ve cellular profiling of the NK cell repertoire in 5000 healthy individuals within the frame of a unique prospective population-based cohort study. A refined methodological platform is employed to define quantitative metrics of NK cell repertoire diversit y and to explore whether such metrics hold utility as novel immunological biomarkers for outcomes following immunomodulatory therapies in malignant lymphoma. Understanding the cellular and molecular basis behind the formation of highly diverse NK cell rep ertoires and their dynamic functional regulation represent outstanding challenges in immunology. Insights in this area may pave the way for new predictive tools and improved treatments in cancer and possibly other clinical conditions where NK cells have b een implicated, including infectious diseases, autoimmunity, and disorders of pregnancy.