Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation.

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 TH9 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.

Effects of fatty acids on T cell function: role in atherosclerosis.

T cells are among the most common cell types present in atherosclerotic plaques and are increasingly being recognized as a central mediator in atherosclerosis development and progression. At the same time, triglycerides and fatty acids have re-emerged as crucial risk factors for atherosclerosis. Triglycerides and fatty acids are important components of the milieu to which the T cell is exposed from the circulation to the plaque, and increasing evidence shows that fatty acids influence T cell function. In this Review, we discuss the effects of fatty acids on four components of the T cell response - metabolism, activation, proliferation and polarization - and the influence of these changes on the pathogenesis of atherosclerosis. We also discuss how quiescent T cells can undergo a type of metabolic reprogramming induced by exposure to fatty acids in the circulation that influences the subsequent functions of T cells after activation, such as in atherosclerotic plaques.