Dissecting the functional impact of somatic mutations on NK cell memory

Principal Investigator

Scientific interest within the context of the graduate college:

Within the framework of the graduate college “Re-Thinking Health,” our goal is to deepen our understanding of how the innate immune system contributes to both the maintenance of health and the development of chronic inflammatory diseases. While persistent immune memory is essential for long-term protection against infections, it can also hinder therapeutic success in chronic inflammatory conditions. Traditionally associated with the adaptive immune system, immune memory has recently been observed in innate lymphoid cells (ILCs), particularly Natural killer (NK) cells. However, the mechanisms underlying the establishment and maintenance of NK cell memory, as well as its functional consequences for health and disease, remain only partially understood. By investigating ILC and NK cell responses to viral infections and chronic inflammatory environments, we aim to uncover the extrinsic signals, intrinsic cellular characteristics, and molecular networks that drive memory formation and persistence. This integrative approach will not only expand our understanding of innate immune memory but may also reveal actionable targets to counteract pathological memory or harness memory persistence for improved cell-based therapies.

Project description:

Natural killer (NK) cells are innate lymphocytes that play critical roles in immune defense against viral infections and cancer. Although classically regulated by germline-encoded receptors, NK cells can undergo clonal expansion and epigenetic remodeling, acquiring memory-like properties that enhance their responsiveness to specific stimuli – particularly following infection with cytomegalovirus (CMV). Our recent findings reveal the long-term persistence of highly expanded CMV-specific NK cell clones carrying somatic mutations. These mutations are enriched in cancer driver genes and immune-related pathways, suggesting functional consequences that may contribute to clonal selection and persistence. This challenges the conventional view of NK cell regulation and introduces somatic genetic variability as a novel mechanism influencing immune cell fitness. The goal of this project is to investigate the molecular and functional consequences of selected somatic mutations on NK cell proliferation, survival, and effector functions. Through a combination of genetic perturbation and cellular assays, we aim to elucidate how these variants contribute to NK cell clonal expansion and long-term memory, and how they may enhance antiviral responses. These studies will advance our understanding of NK cell biology and could inform novel strategies to optimize NK cell-based immunotherapies for infection and cancer.

Aim 1: Optimization and validation of targeted gene editing. Building on up-and-running gene editing methods (CRISPR/Cas9, Cytosine-base editing), we will optimize and validate efficient gene-targeting approaches in primary NK cells to model selected loss-of-function candidates.

Aim 2: Characterizing the functional impact of candidate mutations. We will utilize established in vitro assays to assess the consequences of candidate variants on NK cell effector functions, proliferation, and survival in response to different stimuli. If time allows, these assays might be extended by a murine model of CMV infection.

Application details

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