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IEL respond to epithelial cell-derived IL-15, which is complexed to the IL-15 receptor \u03b1 chain (IL-15\/R\u03b1). IL-15 is essential both for maintaining IEL homeostasis and inducing IEL responses to epithelial stress, which has been associated with Coeliac disease. Here, we apply quantitative mass spectrometry to IL-15\/R\u03b1-stimulated IEL to investigate how IL-15 directly regulates inflammatory functions of IEL. IL-15\/R\u03b1 drives IEL activation through cell cycle regulation, upregulation of metabolic machinery and expression of a select repertoire of cell surface receptors. IL-15\/R\u03b1 selectively upregulates the Ser\/Thr kinases PIM1 and PIM2, which are essential for IEL to proliferate, grow and upregulate granzyme B in response to inflammatory IL-15. Notably, IEL from patients with Coeliac disease have high PIM expression. Together, these data indicate PIM kinases as important effectors of IEL responses to inflammatory IL-15.<\/jats:p>","DOI":"10.1038\/s41467-021-24473-2","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T06:24:02Z","timestamp":1626157442000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes"],"prefix":"10.1038","volume":"12","author":[{"given":"Olivia J.","family":"James","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Vandereyken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8823-9718","authenticated-orcid":false,"given":"Julia M.","family":"Marchingo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"Bray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Love","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3977-3425","authenticated-orcid":false,"given":"Mahima","family":"Swamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"24473_CR1","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/ni1101-997","volume":"2","author":"A Hayday","year":"2001","unstructured":"Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997\u20131003 (2001).","journal-title":"Nat. Immunol."},{"key":"24473_CR2","doi-asserted-by":"crossref","unstructured":"Mayassi, T. & Jabri, B. Human intraepithelial lymphocytes. Mucosal Immunol. 11, 1281\u20131289 (2018).","DOI":"10.1038\/s41385-018-0016-5"},{"key":"24473_CR3","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nri3919","volume":"15","author":"B Jabri","year":"2015","unstructured":"Jabri, B. & Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat. Rev. Immunol. 15, 771\u2013783 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"24473_CR4","doi-asserted-by":"publisher","first-page":"1044 LP","DOI":"10.4049\/jimmunol.0900420","volume":"183","author":"LJ Ma","year":"2009","unstructured":"Ma, L. J., Acero, L. F., Zal, T. & Schluns, K. S. 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