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

TY - JOUR

T1 - IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes

AU - James, Olivia J.

AU - Vandereyken, Maud

AU - Marchingo, Julia M.

AU - Singh, Francois

AU - Bray, Susan E.

AU - Wilson, Jamie

AU - Love, Andrew G.

AU - Swamy, Mahima

N1 - Wellcome Trust PhD studentship to Olivia James (215309/Z/19/Z) and by the Wellcome Trust and Royal Society (Sir Henry Dale Fellowship to Mahima Swamy, 206246/Z/17/Z).

PY - 2021/7/13

Y1 - 2021/7/13

N2 - 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.

AB - 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.

KW - T cells

KW - Interleukins

KW - Mucosal immunology

UR - https://www.scopus.com/pages/publications/85110518167

U2 - 10.1038/s41467-021-24473-2

DO - 10.1038/s41467-021-24473-2

M3 - Article

C2 - 34257288

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

M1 - 4290

ER -