Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells

Charlène Niogret, S. M. Shahjahan Miah, Giorgia Rota, Nicolas P. Fonta, Haiping Wang, Werner Held, Walter Birchmeier, Veronica Sexl, Wentian Yang, Eric Vivier, Ping-Chih Ho, Laurent Brossay () and Greta Guarda ()
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Charlène Niogret: University of Lausanne
S. M. Shahjahan Miah: Brown University Alpert Medical School
Giorgia Rota: University of Lausanne
Nicolas P. Fonta: University of Lausanne
Haiping Wang: University of Lausanne
Werner Held: University of Lausanne
Walter Birchmeier: Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Society
Veronica Sexl: University of Veterinary Medicine
Wentian Yang: Rhode Island Hospital and Brown University Alpert Medical School
Eric Vivier: Aix Marseille Université, Inserm, CNRS, Avenue de Luminy
Ping-Chih Ho: University of Lausanne
Laurent Brossay: Brown University Alpert Medical School
Greta Guarda: University of Lausanne

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The phosphatase Shp-2 was implicated in NK cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear. Here we show, using mice conditionally deficient for Shp-2 in the NK lineage, that NK cell development and responsiveness are largely unaffected. Instead, we find that Shp-2 serves mainly to enforce NK cell responses to activation by IL-15 and IL-2. Shp-2-deficient NK cells have reduced proliferation and survival when treated with high dose IL-15 or IL-2. Mechanistically, Shp-2 deficiency hampers acute IL-15 stimulation-induced raise in glycolytic and respiration rates, and causes a dramatic defect in ERK activation. Moreover, inhibition of the ERK and mTOR cascades largely phenocopies the defect observed in the absence of Shp-2. Together, our data reveal a critical function of Shp-2 as a molecular nexus bridging acute IL-15 signaling with downstream metabolic burst and NK cell expansion.

Date: 2019
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DOI: 10.1038/s41467-019-09431-3

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