Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

Aline Pfefferle, Benedikt Jacobs, Herman Netskar, Eivind Heggernes Ask, Susanne Lorenz, Trevor Clancy, Jodie P. Goodridge, Ebba Sohlberg, Karl Johan Malmberg

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2284-2294
Number of pages11
JournalCell Reports
Volume29
Issue number8
DOIs
Publication statusPublished - 19 Nov 2019
Externally publishedYes

Keywords

  • differentiation
  • education
  • homeostasis
  • IL-15
  • killer cell immunoglobulin-like receptors
  • natural killer cells
  • plasticity
  • single-cell RNA sequencing

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