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

Journal of immunology (Baltimore, Md. : 1950) 2020 Nov 15

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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. Copyright © 2020 by The American Association of Immunologists, Inc.

Citation

Ansel P Nalin, Jesse J Kowalski, Alexander C Sprague, Blaire K Schumacher, Adam G Gerhardt, Youssef Youssef, Kiran V Vedantam, Xiaoli Zhang, Christian W Siebel, Emily M Mace, Michael A Caligiuri, Bethany L Mundy-Bosse, Aharon G Freud. Notch Regulates Innate Lymphoid Cell Plasticity during Human NK Cell Development. Journal of immunology (Baltimore, Md. : 1950). 2020 Nov 15;205(10):2679-2693