RT Journal Article SR Electronic T1 Aging Boosts Antiviral CD8+T Cell Memory Through Improved Engagement Of Diversified Recall Response Determinants JF bioRxiv FD Cold Spring Harbor Laboratory SP 450072 DO 10.1101/450072 A1 Bennett Davenport A1 Jens Eberlein A1 Tom T. Nguyen A1 Francisco Victorino A1 Kevin Jhun A1 Haedar Abuirqeba A1 Verena van der Heide A1 Peter Heeger A1 Dirk Homann YR 2018 UL http://biorxiv.org/content/early/2018/10/22/450072.abstract AB 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 are consistent with the recently proposed “rebound model” that stipulates a gradual alignment of naïve and CD8+TM properties, and identify a diversified collection of potential targets that may be exploited for the therapeutic modulation of CD8+TM immunity.ABBREVIATIONSAICDactivation-induced cell deathATadoptive transferAT/RCadoptive transfer/re-challengeAT/RC Armadoptive transfer/re-challenge with LCMV ArmstrongAT/RC cl13adoptive transfer/re-challenge with LCMV cl13BMPbone morphogenetic proteinCTLcytotoxic T lymphocyteGFPgreen-fluorescent proteinGP, NPglycoprotein, nucleoproteinGSEAgene set enrichment analysisIo, IIo, IIIoprimary, secondary, tertiaryKEGGKyoto Encyclopedia of Genes and GenomesLCMVlymphocytic choriomeningitis virusLCMV ArmLCMV Armstrong (clone 53b)LCMV cl13LCMV clone 13LMListeria monocytogenesLNlymph nodeO, Yold, youngp14 (TCRtg)TCRtg CD8+T cells specific for the LCMV-GP33-41 determinantPBMCperipheral blood mononuclear cellspfuplaque forming unitsSAPSLAM-associated proteinSLAMFsignaling lymphocyte activation molecule familySTAT, pSTATsignal transducer and activator of transcription, phosphorylated STATT cell subsetsTEeffector T cellsTEMeffector memory T cells (CD62Llo/CCR7-)TCMcentral memory T cells (CD62Lhi/CCR7+)TMmemory T cellsTMPmemory-phenotype T cells (CD44hi)TNnaïve T cells (CD44lo)TREGregulatory T cellsTCRtgT cell receptor transgenicTSLPThymic stromal lymphopoietin