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

• Published in: Nature communications Vol. 10; no. 1; pp. 1444 - 14
• Main Authors: Niogret, Charlène, Miah, S. M. Shahjahan, Rota, Giorgia, Fonta, Nicolas P., Wang, Haiping, Held, Werner, Birchmeier, Walter, Sexl, Veronica, Yang, Wentian, Vivier, Eric, Ho, Ping-Chih, Brossay, Laurent, Guarda, Greta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-03-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/95; 631/250/127/1213; 631/250/1619/382; 631/250/516; 631/80/83/2359; 64/60; 96/31; 96/95; Animals; Antigens, Ly - metabolism; Cascades; Cell activation; Cell Count; Cell proliferation; Cell Proliferation - drug effects; Cell Size - drug effects; Downstream; Enzyme Activation - drug effects; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glycolysis; Humanities and Social Sciences; Immunology; Innate immunity; Integrases - metabolism; Interleukin 15; Interleukin 15 receptors; Interleukin 2; Interleukin-15 - pharmacology; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Life Sciences; Metabolism; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Muromegalovirus - physiology; Natural Cytotoxicity Triggering Receptor 1 - metabolism; Natural killer cells; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Receptors; Receptors, Interleukin-15 - metabolism; Science; Science (multidisciplinary); SHP-2 protein; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09431-3

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
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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.
The phosphatase Shp-2 was implicated in NK cell education due to its reported association with inhibitory receptors, but its function in this context is unclear. Here the authors show that Shp-2 is not required for NK cell function, but is necessary for IL-15-induced metabolic burst and expansion.