IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes

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.

Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes

“…T-IEL also express Granzyme C (GzmC) and K (GzmK), although at <100,000 molecules per cell each ( Figure 2b ), making their general expression of Granzymes either comparable to, or higher than, in vitro-generated CTL. This substantial commitment to Granzyme expression is consistent with the expression of the whole cytotoxic machinery, including perforin and key molecules involved in degranulation ( James et al, 2021 ), all of which are either barely detectable, or altogether absent, in the naïve T cells. Thus, these data support the hypothesis that all T-IEL in the gut are geared towards cytotoxic activity.…”

“…It is also interesting to note that amino acid transporters were expressed at very low levels in T-IEL, thus limiting amino acid availability for protein translation. In this context, we recently showed that activation of T-IEL with IL-15 involves both upregulation of ribosome biogenesis and upregulation of amino acid transporters ( James et al, 2021 ). The low rates of protein translation also highlight the importance of studying the proteome in T-IEL as there may be a significant disconnect between protein and mRNA expression.…”

Rewiring of the TCR signalosome in natural intestinal Intraepithelial T lymphocytes drives non-deletional tolerance

“…6A). Data mining our previous proteomic analyses, we found that natural T-IEL expressed lower/absent levels of the LAT protein than conventional TCRβ + CD8αβ + T cells and induced T-IEL, ( 43 ) (Fig. 6B).…”

The role of interleukin-15 in the development and treatment of hematological malignancies

“…Mucosa-associated T-cell subpopulations are mainly CD8+ T-cells and can proliferate and expand after an IL-15 stimulus. IL-15 is overexpressed in lamina propria and intestinal epithelium of patients affected by CD and manages intraepithelial lymphocyte homeostasis between their defense role and uncontrolled inflammation and malignant transformation ( 49 , 50 ).…”