Highlights d ATG4s promote phagophore growth independently of their protease activity and ATG8s d ATG4s and their proximal partners including LRBA regulate ATG9A vesicle trafficking d AI-directed 3D EM reveals that ATG4s promote phagophore-ER contacts during mitophagy d ATG4s are not crucial for ATG8 removal from autolysosomes but can regulate ATG8ylation

Virtual memory T (T VM) cells are antigen-naïve CD8 + T cells that exist in a semidifferentiated 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.

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