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Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. <jats:italic>Tsc1<\/jats:italic> is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of <jats:italic>Tsc1<\/jats:italic> causes a marked decrease in the number of NK cells and compromises rejection of \u2018missing-self\u2019 haematopoietic tumours and allogeneic bone marrow. The residual <jats:italic>Tsc1<\/jats:italic>-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of <jats:italic>Raptor<\/jats:italic>, a component of mTORC1, largely reverses these defects. <jats:italic>Tsc1<\/jats:italic>-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development.<\/jats:p>","DOI":"10.1038\/ncomms12730","type":"journal-article","created":{"date-parts":[[2016,9,7]],"date-time":"2016-09-07T10:33:29Z","timestamp":1473244409000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation"],"prefix":"10.1038","volume":"7","author":[{"given":"Meixiang","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junming","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuande","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanwen","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panglian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zai","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjun","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,7]]},"reference":[{"key":"BFncomms12730_CR1","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1073\/pnas.92.2.377","volume":"92","author":"JP DiSanto","year":"1995","unstructured":"DiSanto, J. 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