Interleukin-7R and chemokine receptor type 7 differentially regulate metabolism in CD4+ and CD8+ T cells

Naïve T cells are highly metabolically active, maintaining homeostatic function as well as continuously moving and surveying lymph nodes for dendritic cells (DCs) presenting cognate antigen. T-cell metabolism is thought to change throughout development: Naïve T cells have been found to predominantly utilize catabolism for naïve T-cell homeostasis while T-cell activation leads effector T cells to become glycolytic. There is still relatively less known about how individual and combinations of molecular signals drive specific metabolic programs in naïve T cells. Naïve T cells primarily depend on IL-7 signaling to IL-7R for homeostasis and are driven by the chemokine receptor CCR7 responding to CCL21 for rapid motility in lymph nodes, leading to T-cell surveillance. We identify specific roles for IL-7R and CCR7 in driving differential metabolic programs in naïve CD8+ and CD4+ T cells. We find that while IL-7 treatment increases glycolysis in both naïve CD4+ and CD8+ T cells, CCL21 treatment does not affect glycolysis. Instead, CCR7 signaling decreases respiratory capacity and mitochondrial intensity and area. While IL-7 treatment does not impact overall oxidative phosphorylation, IL-7 also alters mitochondrial dynamics. Interestingly, a combination of IL-7R and CCR7 signaling using IL-7 with CCL21 differentially affects CD4+ versus CD8+ T-cell metabolism. Our results demonstrate that multiple molecular signals can differentially regulate naïve CD4+ and CD8+ T-cell metabolism, leading to changes in both glycolysis and oxidative phosphorylation in naïve T cells.