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Oleic acid triggers CD4+ T cells to be metabolically rewired and poised to differentiate into proinflammatory T cell subsets upon activation

Reilly, N. A.; Sonnet, F.; Dekkers, K. F.; Kwekkeboom, J. C.; Sinke, L.; Hilt, S.; Suleiman, H. M.; Hoeksema, M. A.; Mei, H.; van Zwet, E. W.; Everts, B.; Ioan-Facsinay, A.; Jukema, J. W.; Heijmans, B. T.

2024-02-21 genomics
10.1101/2024.02.16.580665 bioRxiv
Show 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, results in a preferential differentiation into pro-inflammatory subsets upon activation by upregulating core metabolic pathways. RNA-sequencing of non-activated CD4+ T cells revealed that oleic acid upregulates genes encoding enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis linked this rewiring to the differentiation of pro-inflammatory subsets. Indeed, spectral flow cytometry showed that pre-exposure to oleic acid results in a skew toward IL-9, IL-17A, IL-5 and IL-13 producing T cells upon activation. Importantly, inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, fatty acids may affect inflammatory diseases by influencing T cell metabolism.

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