Abstract
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.
Highlights
Immune protection provided by antiviral memory T cells relies in part on their capacity for prodigious proliferative expansion in the context of a re-infection, a proficiency that, perhaps surprisingly, is augmented rather than curtailed as memory T cells progress with age
In the present work, which draws on emerging evidence that T cell memory is not a stable trait but a progressively evolving property, we have begun to elucidate the mechanistic foundations for this age-associated amplification of memory T cell recall potential
CD8+TM populations were enriched from the congenic donors, combined at a ratio of 1:1 at the level of CD8+TM specific for the immunodominant lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) determinant NP396–404 (DbNP396+CD8+TM), and injected into congenic recipients that were subsequently inoculated with LCMV; the respective expansions of young vs. old DbNP396+CD8+TM-derived IIo CD8+TE populations were quantified eight days later (Fig 1A)
Summary
CD62L expression by peripheral CD8+TM generated in response to an acute pathogen challenge is progressively enhanced as a function of original priming conditions and infection history; upon entry into certain lymphoid or nonlymphoid tissues, CD8+TMexpressed CD62L is reduced; and CD8+TEM and TCM subsets themselves are subject to gradual adaptations that introduce an array of molecular, phenotypic and functional changes including, importantly, an increase of their respective recall capacities [2, 5,6,7,8,9,10] Both CD62Llo and CD62Lhi CD8+T cell populations exhibit a broad spectrum of dynamically regulated properties that cannot be captured by the simple phenomenological distinction of TEM and TCM subsets.
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