Cell Reports
Volume 29, Issue 8, 19 November 2019, Pages 2284-2294.e4
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Article
Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

https://doi.org/10.1016/j.celrep.2019.10.058Get rights and content
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Highlights

  • mTOR-dependent hierarchy determines proliferative capacity of NK cells

  • NK cell education is an inheritable state during cell division

  • Intra-lineage plasticity maintains phenotypic and functional NK cell homeostasis

  • The acquired phenotype determines functional potential in NK cells

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.

Keywords

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

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