FcRγ Gene Editing Reprograms Conventional NK Cells to Display Key Features of Adaptive Human NK Cells

Weiru Liu; Jeannine M Scott; Emma Langguth; Helena Chang; Peter H Park; Sungjin Kim

doi:10.1016/j.isci.2020.101709

FcRγ Gene Editing Reprograms Conventional NK Cells to Display Key Features of Adaptive Human NK Cells

iScience. 2020 Oct 20;23(11):101709. doi: 10.1016/j.isci.2020.101709. eCollection 2020 Nov 20.

Authors

Weiru Liu^{1

2}, Jeannine M Scott³, Emma Langguth¹, Helena Chang¹, Peter H Park¹, Sungjin Kim^{1

4}

Affiliations

¹ Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
² Biochemistry, Molecular, Cellular and Developmental Biology Graduate Group, University of California, Davis, USA.
³ Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
⁴ Department of Microbiology and Immunology, University of California, Davis, CA 95616, USA.

Abstract

Adaptive human natural killer (NK) cells display significantly enhanced responsiveness to a broad-range of antibody-bound targets through the engagement of CD16 compared to conventional NK cells, yet direct reactivity against tumor targets is generally reduced. Adaptive NK cells also display a distinct phenotype and differential expression of numerous genes, including reduced expression of signaling adapter FcRγ and transcription factor PLZF. However, it is unclear whether differential expression of specific genes is responsible for the characteristics of adaptive NK cells. Using CRISPR-Cas9, we show deletion of FcRγ in conventional NK cells led to enhanced CD16 responsiveness, abolished cell surface expression of natural cytotoxicity receptors, NKp46 and NKp30, and dramatically reduced responsiveness to K562 and Raji tumor cells. However, deletion of PLZF had no notable effects. These results suggest multiple roles for FcRγ and identify its deficiency as an important factor responsible for the functional and phenotypic characteristics exhibited by adaptive NK cells.

Keywords: Cancer; Immunology; Molecular Biology.

Grants and funding

R01 AI110894/AI/NIAID NIH HHS/United States