Spatiotemporal regulation of energetic charge dictates T cell function.

Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.