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Downloaded in Aug 2019 ARTICLE https://doi.org/10.1038/s41467-021-24473-2 OPEN IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes Olivia J. James1, Maud Vandereyken1, Julia M. Marchingo 2, Francois Singh1, Susan E. Bray3, Jamie Wilson4, ✉ Andrew G. Love1 & Mahima Swamy 1 1234567890():,; 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 upregu- lates 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. 1 MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK. 2 Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. 3 NHS Research Scotland, Tayside Tissue Biorepository, University of Dundee, Dundee, UK. 4 Department of ✉ Pathology, NHS Tayside, Ninewells Hospital, Dundee, UK. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:4290 | https://doi.org/10.1038/s41467-021-24473-2 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24473-2 ntraepithelial lymphocytes (IEL) are a specialised lymphoid Here, we investigate the intrinsic effects of exposure to elevated compartment in the intestinal epithelium, comprising a het- levels of IL-15 on IEL. We take a systematic unbiased approach I 1 fi erogeneous population of T lymphocytes . IEL express either using high-resolution quantitative proteomics to de ne the global the αβ T cell antigen receptor (TCR) or the γδ TCR, alongside changes induced in purified TCRγδCD8αα, TCRαβCD8αα and TCR co-receptors CD8αβ or CD8αα and to a lesser extent CD4 TCRαβCD8αβ IEL subpopulations after 24 h exposure to IL-15. (+/−). The most prevalent IEL subsets within the epithelium of the Our data show how IL-15 regulates the activation status of IEL mouse small intestine are those expressing TCRγδ and CD8αα through the upregulation of various activating and inhibitory (TCRγδCD8αα), which account for ~50% of the total IEL pool, receptors, biosynthetic and bioenergetic activation, and induction with the remaining mostly being TCRαβCD8αβ or TCRαβCD8αα- of proliferation. Importantly, these data reveal a critical role for expressing cells. In human guts, TCRαβCD8αβ and TCRαβCD4 the proto-oncogenes PIM1 and PIM2 kinases in IL-15-induced make-up the majority of IEL, with TCRγδ IEL contributing proliferation, growth, and acquisition of effector function in IEL. <5–20% of the IEL compartment2. IEL are constantly exposed to commensal bacteria, dietary antigens, and potential pathogens at the intestinal epithelium, and are tasked with responding to epi- Results thelial stress and protecting the intestinal barrier from external Proteome profiling reveals distinct features of IL-15/Rα sti- insults. How IEL get activated is a matter of debate; but IEL do not mulated IEL. Here, we used quantitative label-free high-resolu- solely depend on TCR stimulation for their activation, rather, tion mass spectrometry to explore how IL-15 shapes the signals from the microenvironment are important for commu- proteome of the main mouse IEL subsets: TCRαβCD8αβ, nicating compromised barrier integrity to the surrounding IEL TCRαβCD8αα and TCRγδCD8αα (Supplementary Fig. 1a). and eliciting an effective immune response. One such signal is the Importantly, we used IL-15/Rα complexes to better mimic the γ γ common -chain ( c) family cytokine IL-15. trans-presentation of IL-15 by IEC, and because it is more IL-15 is produced by a wide range of cells including non- representative of physiological conditions17,18. For IL-15-induced hematopoietic cells such as intestinal epithelial cells (IEC) and its activation, IEL were treated for 24 h with 100 ng/mL IL-15/Rα expression is elevated in the gut microenvironment during tissue (3.4 nM), based on pSTAT5 induction (Supplementary Fig. 1b) stress or infection3. IL-15 is commonly presented to surrounding and higher survival (Fig. 1a) observed at this concentration. IEL in a cell contact-dependent manner, known as trans-pre- Untreated controls were derived directly ex vivo, as IEL do not sentation, by IEC expressing IL-15 bound to the high-affinity IL- survive well in culture with low concentrations, or in complete 15 receptor α subunit (IL-15Rα)4. IL-15/Rα interacts with the β absence of IL-15 (Fig. 1a). γ fi fi (CD122) and c subunits present on the surface of IEL, initiating We identi ed and quanti ed >7500 proteins in the total dataset JAK/STAT-mediated signalling events that alter lymphocyte (4 biological replicates/population; ±IL-15/Rα), providing high- function5. It is well established that IEL require IL-15 for their resolution quantitative proteomes of three developmentally survival in the small intestine6, and development and maturation diverse IEL populations. Intensities were converted into estimated of CD8αα IEL can be rescued in IL-15Rα−/− mice by restoring protein copy number per cell using the proteomic histone ruler IL-15Rα expression to the intestinal epithelium4. method19,20. Both intensities and copy numbers showed good IL-15 impacts more than just IEL survival. IL-15 induces correlation between replicates and subsets, despite their differ- proliferation and cytolytic effector function in human IEL ences in ontogeny. All IEL subsets had similar protein content in vitro7. Importantly, elevated intestinal IL-15 expression is (~40–50 pg/cell), and this was not significantly changed by IL-15 associated with increased numbers of cytotoxic IEL in the small (Fig. 1b). These data indicate that different IEL subsets are similar intestine of Coeliac disease (CeD) patients8, attributed to IL-15- in their protein make-up and overall protein abundance driven survival and proliferative expansion of IEL9,10. CeD is an (Supplementary Fig. 1c, d). autoimmune enteropathy whereby genetically susceptible indivi- To investigate how IL-15 differentially altered the proteomic duals have an adverse reaction to gluten, causing immune- landscape of each subset, we calculated the fold change in mediated damage to the small intestine. IEL derived from patients expression of proteins (IL-15-treated vs untreated) and found that with CeD have elevated expression of activating NK cell receptors IL-15 largely drove the upregulation of proteins in all IEL subsets such as NKG2D and CD94 and expand massively in response to (Fig. 1c and Supplementary Data 3). Interestingly, IL-15 had the elevated levels of IL-159,11. These findings suggest that regulation strongest impact on TCRαβCD8αβ IEL, with >600 proteins being of epithelial expression of IL-15 is a key mechanism by which IEL significantly upregulated >2-fold, approximately twice as many as activity is controlled. Thus, for IEL to utilise IL-15 as a survival in TCRαβCD8αα and TCRγδCD8αα IEL. This was surprising, as stimulus but also respond to rising levels of IL-15 as a ‘danger TCRαβCD8αβ IEL expressed the lowest copies of IL2Rβ (CD122), signal’, IEL responses to IL-15 must be tightly controlled. How- the IL-15 receptor subunit necessary for signal transduction ever, the mechanism by which IL-15 mediates IEL function is downstream of IL-15 (Supplementary Fig. 1e). However, the poorly understood. phosphorylation of STAT5 both ex vivo and in response to IL-15/ Much of the data we have on effects of IL-15 on IEL have been Rα stimulation was comparable in all three subsets (Supplemen- derived from CeD patients and from ‘healthy’ IEL obtained from tary Fig. 1f). These data suggest that CD122 levels on oesophagus-gastro-duodenoscopies for non-CeD complaints, or TCRαβCD8αβ IEL are sufficient to activate downstream signal- from gastric bypasses for morbidly obese patients11–13. Due to the ling at a similar level to that seen in the other IEL subsets. cell contact-dependent mechanism of IL-15 presentation, it is To identify shared IL-15 targets in IEL, we next asked which likely that IEL from CeD patients, and indeed, other entero- proteins were commonly regulated by IL-15 among IEL subsets. pathies, receive additional stress signals from the IEC that they IL-15/Rα stimulation led to the downregulation of relatively few are in contact with in vivo. For example, the stress-induced proteins, with only 5 being significantly downregulated >2-fold in NKG2D ligands, MIC-A and MIC-B, are elevated on damaged all three IEL subsets (Fig. 1d, Supplementary Data 1). On the IEC in CeD, and can activate IEL11,12,14. IEL are also exposed to other hand, we identified 95 proteins that were significantly IL-21 and interferons in CeD15,16, and it is unclear how many of upregulated >2-fold in all IEL subsets, and >240 proteins these factors are present in so-called healthy human controls. significantly
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