Project description
Mechanisms of rapid response of human NK cells to pathogens
Rapid response to pathogens involves a pool of innate immune effector cells which respond promptly to infection. However, innate cells can differentiate after pathogen encounters and remember past experiences, acquiring memory-like features. Recent studies from the project group have shown that human memory-like natural killer (NK) cells undergo global epigenetic remodelling and expand clonally in response to cytomegalovirus infection. The ultimate goal of the EU-funded MEM-CLONK project is to identify the mechanisms driving the acquisition, selection and maintenance of public and private clonal memory in human NK cells. The working hypothesis is that NK cell clonal expansions might increase NK cell fitness and effector potential but also enhance the risk of oncogenic mutations.
Objective
The pool of innate immune effector cells is wired to rapidly respond to pathogens, whereas only few specificities within the naïve adaptive repertoire expand clonally, undergo epigenetic remodelling and differentiate into effector and memory cells. However, innate cells can differentiate upon pathogen encounter and remember past experiences as well, thereby challenging this strict dichotomy. In particular, us and others have shown that human memory Natural Killer (NK) cells with global epigenetic remodelling can be generated in response to specific signals during cytomegalovirus (CMV) infection. We have recently identified two major types of open chromatin domains in human memory NK (mNK) cells ex vivo: first, a shared signature featured by all mNK cells across CMV-seropositive donors (“public memory”); second, a diverse set of unique open chromatin regions associated with the drastic expansions of individual and stable NK cell clones (“private memory”). Based on this unexpected finding, we hypothesise that the shared and the unique clonal memory might provide mNK cells with increased fitness and high effector potential, but also enhance the risk of oncogenic mutations.
The ultimate goal of this project is to identify the signals and molecular mechanisms driving acquisition, selection and maintenance of human NK cell public and private clonal memory. To this end, we will combine multiomic single cell assays and lineage tracing of human NK cells from healthy donors and patients ex vivo, or under various stimuli in vitro, with genome-wide CRISPR perturbation studies to directly link ex vivo features with functional read outs. Success of this project will not only lead to new insights into the key networks promoting persistence and effector functions of mNK cells, but also reveal promising novel targets for cellular anti-tumour therapies.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
10117 Berlin
Germany