Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
Year: 2019
Type: article
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.
Source: Nature Communications
Institutions: University of Lausanne, Brown University, Institute for Research in Biomedicine, Università della Svizzera italiana, Centre Hospitalier Universitaire Vaudois, Max Delbrück Center, University of Veterinary Medicine Vienna, Rhode Island Hospital, Centre National de la Recherche Scientifique, Inserm, Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille, Innate Pharma (France), Centre d’Immunologie de Marseille-Luminy, Hôpital de la Timone
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,125
Funders: National Science Foundation, Melanoma Research Alliance, Institute for Research in Biomedicine, Novartis Foundation, European Commission, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Université de Lausanne, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, H2020 European Research Council, FP7 Ideas: European Research Council
Awards: Metabolic restriction of tumor infiltrating immune cells leads to immune suppression in the tumor microenvironment, NLRs AS TRANSCRIPTIONAL REGULATORS, T CELL-INTRINSIC ROLE OF PATTERN RECOGNITION RECEPTORS, Regulation of MCMV Persistence by Natural Killer Cells, G434337789, T CELL-INTRINSIC ROLE OF PATTERN RECOGNITION RECEPTORS, NK T Cell Interactions with NK Cells During Viral Infection, Generation and maintenance of conventional and unconventional memory CD8 T cells, Targeting Innate Lymphoid Cells, Role of PTPN11 in Cartilage Stem Cells and Tumorigenesis, NK RECEPTORS AND CD1 ROLES IN NK AND NK T CELL FUNCTION, G9000238298
OpenAlex ID: W2927200130