Periodic Reporting for period 1 - MEM-CLONK (Imprinting and clonality of human NK cell memory)
Período documentado: 2022-09-01 hasta 2025-02-28
The innate immune system is designed to respond quickly to pathogens, while the adaptive immune system typically involves the clonal expansion of a few specific lymphocytes, which undergo epigenetic changes and differentiate into effector and memory cells. However, innate immune cells can also adapt after encountering pathogens and retain a form of memory, blurring this traditional distinction. Notably, research from our team and others has shown that human memory Natural Killer (NK) cells can undergo global epigenetic changes in response to specific signals during cytomegalovirus (CMV) infection.
Our project’s key discovery is that human memory NK cells can expand clonally in response to CMV, a characteristic previously thought to be exclusive to adaptive immune cells with rearranged receptors. Based on this unexpected finding, we propose that clonal memory may give memory NK cells increased fitness and enhanced ability to respond, but it could also raise the risk of oncogenic mutations.
The goal of this project is to identify the signals and molecular mechanisms responsible for the acquisition, selection, and maintenance of human NK cell clonal memory. We will use multiomic single-cell assays and lineage tracing of NK cells from healthy donors and patients, both ex vivo and under various in vitro conditions, alongside genome-wide CRISPR studies to directly link observed features with functional outcomes. Success in this project will not only provide new insights into the key networks that support the persistence and activity of NK cells but also identify promising targets for developing cellular therapies against tumors.
Our project’s key discovery is that human memory NK cells can expand clonally in response to CMV, a characteristic previously thought to be exclusive to adaptive immune cells with rearranged receptors. Based on this unexpected finding, we propose that clonal memory may give memory NK cells increased fitness and enhanced ability to respond, but it could also raise the risk of oncogenic mutations.
The goal of this project is to identify the signals and molecular mechanisms responsible for the acquisition, selection, and maintenance of human NK cell clonal memory. We will use multiomic single-cell assays and lineage tracing of NK cells from healthy donors and patients, both ex vivo and under various in vitro conditions, alongside genome-wide CRISPR studies to directly link observed features with functional outcomes. Success in this project will not only provide new insights into the key networks that support the persistence and activity of NK cells but also identify promising targets for developing cellular therapies against tumors.
Using single-cell multiomic techniques, including lineage barcoding through mitochondrial DNA mutations, we analyzed peripheral blood NK cells from both CMV-seropositive and CMV-seronegative healthy donors. Our findings established a direct connection between epigenetic diversification in memory NK cells and their clonality, providing the first evidence of human innate immune clonality. Additionally, we identified the signals that trigger the acquisition of the inflammatory memory epigenetic signature, characterized by AP1 motif activity, specifically through the combined activation of pro-inflammatory cytokine receptors and the NKG2C receptor. These results were published in Nature Immunology (Rückert et al., 2022) and have been presented at numerous international conferences. Beyond achieving this central aim, ongoing research of the project aims to further uncover the molecular mechanisms that contribute to establishing innate clonal memory.
The research conducted under the MEM-CLONK project has provided the first evidence of clonality in the human innate immune system. We believe this fundamental discovery, along with subsequent findings from the project, aiming at understanding the molecular switches of innate clonality, will significantly transform our understanding of the immune system and potentially lead to clinical advancements in anti-tumor and antiviral therapies.