Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
Benedikt Jacobs
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Herman Netskar
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Eivind Heggernes Ask
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Susanne Lorenz
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
Trevor Clancy
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Jodie P. Goodridge
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Fate Therapeutics, Inc., San Diego, CA, USA
Ebba Sohlberg
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
Karl-Johan Malmberg
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Corresponding author
Summary: Natural killer (NK) cell repertoires are made up of phenotypically distinct subsets with different functional properties. The molecular programs involved in maintaining NK cell repertoire diversity under homeostatic conditions remain elusive. Here, we show that subset-specific NK cell proliferation kinetics correlate with mTOR activation, and global repertoire diversity is maintained through a high degree of intra-lineage subset plasticity during interleukin (IL)-15-driven homeostatic proliferation in vitro. Slowly cycling sorted KIR+CD56dim NK cells with an induced CD57 phenotype display increased functional potential associated with increased transcription of genes involved in adhesion and immune synapse formation. Rapidly cycling cells upregulate NKG2A, display a general loss of functionality, and a transcriptional signature associated with increased apoptosis/cellular stress, actin-remodeling, and nuclear factor κB (NF-κB) activation. These results shed light on the role of intra-lineage plasticity during NK cell homeostasis and suggest that the functional fate of the cell is tightly linked to the acquired phenotype and transcriptional reprogramming. : Unique and genetically hard-wired NK cell repertoires are well-maintained over time despite the rapid turnover of NK cells. Pfefferle et al. identify the role of intra-lineage plasticity during NK cell homeostasis and suggest that a cell’s functional fate is tightly linked to its acquired phenotype as determined by transcriptional reprogramming. Keywords: natural killer cells, homeostasis, plasticity, single-cell RNA sequencing, education, differentiation, killer cell immunoglobulin-like receptors, IL-15
