Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality

Virtual memory T (T-VM) cells are antigen-naive CD8(+) T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (T-MEM) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of T-VM cells and their altered functionality with age, here we investigate T-VM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of T-VM, but not T-MEM, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse T-VM cells and human CD8(+) T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of T-VM, but not T-MEM, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8(+) T cells. Fatty acid oxidation (FAO) is thought to contribute to high spare respiratory capacity (SRC), which in turn affects CD8(+) T cell function. Here, the authors show that ex vivo virtual memory T cells (and not antigen experienced memory T cells) have high SRC, a metabolic state that it is affected by ageing and IL-15 signalling and not directly by FAO.