PT - JOURNAL ARTICLE AU - Bennett Davenport AU - Jens Eberlein AU - Tom T. Nguyen AU - Francisco Victorino AU - Kevin Jhun AU - Haedar Abuirqeba AU - Verena van der Heide AU - Peter Heeger AU - Dirk Homann TI - Aging Boosts Antiviral CD8<sup>+</sup>T Cell Memory Through Improved Engagement Of Diversified Recall Response Determinants AID - 10.1101/450072 DP - 2018 Jan 01 TA - bioRxiv PG - 450072 4099 - http://biorxiv.org/content/early/2018/10/22/450072.short 4100 - http://biorxiv.org/content/early/2018/10/22/450072.full 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