Aging boosts antiviral CD8⁺T cell memory through improved engagement of diversified recall response determinants

The determinants of protective CD8⁺ memory T cell (CD8⁺TM) immunity remain incompletely defined and may in fact constitute an evolving agency as aging CD8⁺TM progressively acquire enhanced rather than impaired recall capacities. Here, we show that old as compared to young antiviral CD8⁺TM more effectively harness disparate molecular processes (cytokine signaling, trafficking, effector functions, and co-stimulation/inhibition) that in concert confer greater secondary reactivity. The relative reliance on these pathways is contingent on the nature of the secondary challenge (greater for chronic than acute viral infections) and over time, aging CD8⁺TM re-establish a dependence on the same accessory signals required for effective priming of naïve CD8⁺T cells in the first place. Thus, our findings reveal a temporal regulation of complementary recall response determinants that is consistent with the recently proposed "rebound model" according to which aging CD8⁺TM properties are gradually aligned with those of naïve CD8⁺T cells; our identification of a broadly diversified collection of immunomodulatory targets may further provide a foundation for the potential therapeutic "tuning" of CD8⁺TM immunity.