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.
Highlights
Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect and maintain the intestinal barrier
IL-15 is produced by a wide range of cells including nonhematopoietic cells such as intestinal epithelial cells (IEC) and its expression is elevated in the gut microenvironment during tissue stress or infection[3]
We used quantitative label-free high-resolution mass spectrometry to explore how IL-15 shapes the proteome of the main mouse IEL subsets: TCRαβCD8αβ, TCRαβCD8αα and TCRγδCD8αα (Supplementary Fig. 1a)
Summary
Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect and maintain the intestinal barrier. 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. Elevated intestinal IL-15 expression is associated with increased numbers of cytotoxic IEL in the small intestine of Coeliac disease (CeD) patients[8], attributed to IL-15driven survival and proliferative expansion of IEL9,10. IEL derived from patients with CeD have elevated expression of activating NK cell receptors such as NKG2D and CD94 and expand massively in response to elevated levels of IL-159,11. These findings suggest that regulation of epithelial expression of IL-15 is a key mechanism by which IEL activity is controlled. The mechanism by which IL-15 mediates IEL function is poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
