IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes
Open Access
- 13 July 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-16
- https://doi.org/10.1038/s41467-021-24473-2
Abstract
Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect and maintain the intestinal barrier. IEL respond to epithelial cell-derived IL-15, which is complexed to the IL-15 receptor α chain (IL-15/Rα). 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/Rα-stimulated IEL to investigate how IL-15 directly regulates inflammatory functions of IEL. IL-15/Rα drives IEL activation through cell cycle regulation, upregulation of metabolic machinery and expression of a select repertoire of cell surface receptors. IL-15/Rα 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.Keywords
Funding Information
- Wellcome Trust (215309/Z/19/Z, 206246/Z/17/Z)
This publication has 62 references indexed in Scilit:
- Human intraepithelial lymphocytesMucosal Immunology, 2018
- IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destructionNature Reviews Immunology, 2015
- Molecular Pathways: Interleukin-15 Signaling in Health and in CancerClinical Cancer Research, 2014
- Intraepithelial lymphocytes in celiac disease immunopathologySeminars in Immunopathology, 2012
- Trans-Presentation of IL-15 by Intestinal Epithelial Cells Drives Development of CD8αα IELsThe Journal of Immunology, 2009
- Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac diseaseGastroenterology, 2003
- Intraepithelial lymphocytes: exploring the Third Way in immunologyNature Immunology, 2001
- Selective expansion of intraepithelial lymphocytes expressing the HLA-E–specific natural killer receptor CD94 in celiac diseaseGastroenterology, 2000
- Interleukin 15 is a potent stimulant of intraepithelial lymphocytesGastroenterology, 1998
- IL-15 Receptor Maintains Lymphoid Homeostasis by Supporting Lymphocyte Homing and ProliferationImmunity, 1998