Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity

Julia A. Wagner, Pamela Wong, Timothy Schappe, Melissa M. Berrien-Elliott, Celia Cubitt, Natalia Jaeger, Madeline Lee, Cassie R. Keppel, Nancy D. Marin, Jennifer A. Foltz, Lynne Marsala, Carly C. Neal, Ryan P. Sullivan, Stephanie E. Schneider, Molly P. Keppel, Nermina Saucier, Megan A. Cooper, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) that mediate antiviral and antitumor responses and require the transcriptional regulator Eomesodermin (Eomes) for early development. However, the role of Eomes and its molecular program in mature NK cell biology is unclear. To address this, we develop a tamoxifen-inducible, type-1-ILC-specific (Ncr1-targeted) cre mouse and combine this with Eomes-floxed mice. Eomes deletion after normal NK cell ontogeny results in a rapid loss of NK cells (but not ILC1s), with a particularly profound effect on penultimately mature stage III NK cells. Mechanisms responsible for stage III reduction include increased apoptosis and impaired maturation from stage II precursors. Induced Eomes deletion also decreases NK cell cytotoxicity and abrogates in vivo rejection of major histocompatibility complex (MHC)-class-I-deficient cells. However, other NK cell functional responses, and stage IV NK cells, are largely preserved. These data indicate that mature NK cells have distinct Eomes-dependent and -independent stages.

Original languageEnglish
Article number107720
JournalCell Reports
Volume31
Issue number9
DOIs
StatePublished - Jun 2 2020

Keywords

  • Eomes
  • NK cell
  • Ncr1-specific
  • cytotoxicity
  • homeostasis
  • in vivo
  • inducible-cre model
  • innate lymphoid cell
  • maturation

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