Notch Regulates Innate Lymphoid Cell Plasticity during Human NK Cell Development.

ABSTRACT: Human NK cells develop in tonsils through discrete NK cell developmental intermediates (NKDIs), yet the mechanistic regulation of this process is unclear. We demonstrate that Notch activation in human tonsil-derived stage 3 (CD34^-CD117⁺CD94^-NKp80^-) and 4A (CD34^-CD117^+/-CD94⁺NKp80^-) NKDIs promoted non-NK innate lymphoid cell differentiation at the expense of NK cell differentiation. In contrast, stage 4B (CD34^-CD117^+/-CD94⁺NKp80⁺) NKDIs were NK cell lineage committed despite Notch activation. Interestingly, whereas NK cell functional maturation from stage 3 and 4A NKDIs was independent of Notch activation, the latter was required for high NKp80 expression and a stage 4B-like phenotype by the NKDI-derived NK cells. The Notch-dependent effects required simultaneous engagement with OP9 stromal cells and were also stage-specific, with NOTCH1 and NOTCH2 receptors regulating stage 3 NKDIs and NOTCH1 primarily regulating stage 4A NKDIs. These data establish stage-specific and stromal-dependent roles for Notch in regulating human NK cell developmental plasticity and maturation.

SUBMITTER: Nalin AP 

PROVIDER: S-EPMC7658047 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature