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 undergo 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 (KIRs). 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 overall goal of the research is to understand the mechanisms governing the formation of human NK cell repertoires and their functional tuning by KIR/HLA interactions. Data generated in this project suggest a new model for how multiple physical cell-to-cell interactions shape the functionality of the cell over time. More specifically, we have shown that signalling through inhibitory receptors leads to accumulation of dense core granules. These structures contain effector molecules such as granzyme B and perforin but also high concentration of bound calcium and act as signalling hubs in the cell (Goodridge et al., Nature Communication 2019). Current investigations, supported by a follow up grant (Toppforsk) from RCN, aim at deciphering how the acidic compartment contribute to lymphocyte function, with the ultimate aim of implementing such knowledge in new cell therapies. Understanding the cellular and molecular basis behind the formation of highly diverse NK cell repertoires 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 been implicated, including infectious diseases, autoimmunity, and disorders of pregnancy. In line with this ambition we have designed a clinical trial with NK cells for patients with advanced leukemia to be launched 2021.

1) New predictive serum protein biomarker in DLBCL based on systems-level immune monitoring: Ask et al, Ms in revision for MED 2) New insights into the functional maturation of human NK cells (Goodridge et al, Nature Communications 3) New insights into the functional plasticity of human NK cells (Pfefferle et al., Cell Reports) 4) New industrial collaborations regarding functional modulation of NK cells and generation of new cell therapy. 5) Design of a new NK cell therapy protocol. Phase I trial to begin in 2021.

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.