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Activation of the mammalian\/mechanistic target of rapamycin (mTOR<\/jats:styled-content>) pathway has been implicated in regulating the differentiation of effector and memory T cells. However, the mechanisms that control mTOR<\/jats:styled-content> activity during immunity to tumours and infections are not well known. Activation of co\u2010stimulatory receptors, including CD<\/jats:styled-content>28 and natural killer group 2D (NKG<\/jats:styled-content>2D), activate phosphatidylinositol\u20103 kinase and subsequently may activate the mTOR<\/jats:styled-content> pathway in CD<\/jats:styled-content>8+<\/jats:sup> T cells. This study compared the activation of the mTOR<\/jats:styled-content> signalling pathway after co\u2010stimulation through CD<\/jats:styled-content>28 or NKG<\/jats:styled-content>2D receptors in murine effector CD<\/jats:styled-content>8+<\/jats:sup> T cells. Compared with CD<\/jats:styled-content>28 co\u2010stimulation, activation through CD<\/jats:styled-content>3 and NKG<\/jats:styled-content>2D receptors had weaker activation of mTOR<\/jats:styled-content>c1, as shown by decreased phosphorylation of mTOR<\/jats:styled-content>c1 targets S6K1, ribosomal protein S6 and eukaryotic initiation factor 4E binding protein 1. NKG<\/jats:styled-content>2D co\u2010stimulation also showed increased gene expression of tuberous sclerosis protein 2, a negative regulator of mTOR<\/jats:styled-content>c1, whereas CD<\/jats:styled-content>28 co\u2010stimulation increased gene expression of Ras homologue enriched in brain, an activator of mTOR<\/jats:styled-content>c1, and hypoxia\u2010inducible factor\u20101\u03b1<\/jats:italic> and vascular endothelial growth factor\u2010\u03b1<\/jats:italic>, pro\u2010angiogenic factors downstream of mTOR<\/jats:styled-content>c1. Strong mTOR<\/jats:styled-content>c1 activation in CD<\/jats:styled-content>28\u2010co\u2010stimulated cells also increased expression of transcription factors that support effector cell differentiation, namely T\u2010bet, B lymphocyte\u2010induced maturation protein (BLIMP\u20101), interferon regulatory factor 4, and inhibitor of DNA binding 2, whereas low levels of mTOR<\/jats:styled-content>c1 activation allowed for the expression of Eomes, B\u2010cell lymphoma 6 (BCL6), and inhibitor of DNA binding 3 during NKG<\/jats:styled-content>2D stimulation, and increased expression of memory markers CD<\/jats:styled-content>62 ligand and CD<\/jats:styled-content>127. These data show that compared with CD<\/jats:styled-content>28, co\u2010stimulation through the NKG<\/jats:styled-content>2D receptor leads to the differential activation of the mTOR<\/jats:styled-content> signalling pathway and potentially supports memory CD<\/jats:styled-content>8+<\/jats:sup> T\u2010cell differentiation.<\/jats:p>","DOI":"10.1111\/imm.12563","type":"journal-article","created":{"date-parts":[[2015,12,12]],"date-time":"2015-12-12T15:13:44Z","timestamp":1449933224000},"page":"305-320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Natural killer group 2D and CD<\/scp>28 receptors differentially activate mammalian\/mechanistic target of rapamycin to alter murine effector CD<\/scp>8+<\/sup> T\u2010cell differentiation"],"prefix":"10.1111","volume":"147","author":[{"given":"Bryan","family":"McQueen","sequence":"first","affiliation":[{"name":"Department of Biological and Environmental Sciences 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