Linoleic acid-mediated regulation of T cell cytokine-subset composition in a murine model of type 1 diabetes
Hernandez Escalante, Jaileene
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Type 1 Diabetes (T1D) is a complex autoimmune disorder in which T cells destroy the pancreatic islets, leading to a loss of insulin production and hyperglycemia. The disease incidence has increased globally over the last decades, primarily in individuals with low to moderate genetic risk. There is evidence that environmental factors play a role alongside genetic risk to trigger the disease. An environmental factor that has global influence is adoption of the Western diet, characterized by increased consumption of n-6 fatty acids, including linoleic acid (LA), and decreased consumption of n-3 fatty acids. Increased n-6/n-3 ratios are associated with enhanced susceptibility to autoimmune diseases. We sought to understand how linoleic acid affects the survival and function of T cells from the non-obese diabetic (NOD) mouse, a model for T1D. We found that linoleic acid's presence during in vitro activation of T cells led to an increased expansion of the cells in culture. Additionally, CD4+ and CD8+ T cells activated in linoleic acid's presence produced increased levels of pro-diabetogenic cytokines, including Interleukin-21 (IL-21) and Interferon-gamma (IFN-γ). In contrast, linoleic acid reduced IL-10-producing CD4+ T cells, which are protective in T1D, significantly changing the balance between pro-and anti-inflammatory T cell subsets. Gene expression analysis of T cells exposed to linoleic acid during in vitro activation revealed decreased gene expression of lipid-regulated transcription factors, peroxisome proliferator-activated receptors (PPAR), PPARα and PPARγ. These data suggest a role for these transcription factors and their associated pathways in linoleic acid-mediated T cell functions. Finally, we tested whether the T cell fatty acid response is regulated by the cytokine IL-7, which modulates T cell immunometabolism. However, our data did not reveal a prominent role for IL-7 in regulating the T cell response to linoleic acid. Together, these studies add to evidence that fatty acids present in the microenvironment can directly alter T cell functions and that changes in dietary components may contribute to enhanced T1D susceptibility.