Aging Of Antiviral CD8+ Memory T Cells Fosters Increased Survival, Metabolic Adaptations And Lymphoid Tissue Homing

Abstract

ABSTRACTAging of established antiviral T cell memory fosters a series of progressive adaptations that paradoxically improve rather than compromise protective CD8+T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (CD8+TM) homeostasis. Over time, CD8+TM become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+TM quiescence and fitness but also impart the re-acquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+TM accumulations in bone marrow, splenic white pulp and particularly lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+TM poised for greater recall responses.ABBREVIATIONSATadoptive transferATGLadipose triglyceride lipaseBMPblood and marginated poolFA, FAO, FAS, FASNfatty acid, fatty acid oxidation, fatty acid synthesis, fatty acid synthaseFSC, SSCforward scatter, side scatterGMFIgeometric mean of fluorescence intensityGP, NPglycoprotein, nucleoproteinGSEAgene set enrichment analysisGSHglutathioneIo, IIoprimary, secondaryKEGGKyoto Encyclopedia of Genes and GenomesLALlysosomal acid lipase (LIPA)LCMVlymphocytic choriomeningitis virusNESnormalized enrichment scoreNLTsnonlymphoid tissuesO, Yold, youngOxPhosoxidative phosphorylationp14 cellsTCRtg CD8+T cells specific for the LCMV-GP33-41 determinantRP, WPred pulp, white pulp (spleen)T cell subsetsTEeffector T cellsTCMcentral memory T cells (CD62Lhi)TEMeffector memory T cells (CD62Llo)TEMRAterminally differentiated CD45RA+ effector memory T cells (human)TMmemory T cellsTMPmemory-phenotype T cells (CD44hi)TNnaïve T cells (CD44lo)TRMresident memory T cells (CD69/CD103-enriched)TCRtgT cell receptor transgenicTSLPThymic stromal lymphopoietin