Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation
Nathalie A. Reilly, Friederike Sonnet, Koen F. Dekkers, Joanneke C. Kwekkeboom, Lucy Sinke, Stan T. Hilt, Hayat M. Suleiman, Marten A. Hoeksema, Hailiang Mei, Erik W. van Zwet, Bart Everts, Andreea Ioan‐Facsinay, J. Wouter Jukema, Bastiaan T. Heijmans
Abstract
T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4 + T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward T H 9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9 + -producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.