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.
Highlights
The phosphatase Shp-2 was implicated in Natural killer (NK) cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear
NK cell inhibitory receptor signaling is mediated by phosphatases, including the SH2-containing inositol phosphatase-1 (SHIP-1) and the crucial SH2 domain-containing tyrosine phosphatase-1 (Shp-1)[7,8,9,10,11], which is recruited to the inhibitory receptor immunoreceptor tyrosine-based inhibitory motifs (ITIM) upon engagement
Ptpn11fl/fl mice were crossed to the Ncr1creKi deleter strain[15,23]
Summary
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. Confirming the critical role of inhibitory receptor engagement in NK cell education, Shp-1-deficient NK cells are hyporesponsive. The absence of Shp-2 is disadvantageous when NK cells are exposed to high IL-15 doses This phenotype is linked to a markedly impaired engagement of ERK and to a compromised metabolic activation. In agreement with these findings, Shp-2-deficient Ly49H+ NK cells have defective proliferation during MCMV infection. Taken together, these data uncover an unanticipated role of Shp-2 in NK cells, identifying this phosphatase as an essential node in NK cell metabolism downstream of the IL-15 receptor
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