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

ABSTRACT Aging 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 + T M ) homeostasis. Over time, CD8 + T M become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8 + T M quiescence and fitness but also impart the re-acquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8 + T M from blood and nonlymphoid tissues to lymphatic organs results in CD8 + T M 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 + T M poised for greater recall responses. ABBREVIATIONS AT adoptive transfer ATGL adipose triglyceride lipase BMP blood and marginated pool FA, FAO, FAS, FASN fatty acid, fatty acid oxidation, fatty acid synthesis, fatty acid synthase FSC, SSC forward scatter, side scatter GMFI geometric mean of fluorescence intensity GP, NP glycoprotein, nucleoprotein GSEA gene set enrichment analysis GSH glutathione I o , II o primary, secondary KEGG Kyoto Encyclopedia of Genes and Genomes LAL lysosomal acid lipase (LIPA) LCMV lymphocytic choriomeningitis virus NES normalized enrichment score NLTs nonlymphoid tissues O, Y old, young OxPhos oxidative phosphorylation p14 cells TCRtg CD8 + T cells specific for the LCMV-GP 33-41 determinant RP, WP red pulp, white pulp (spleen) T cell subsets T E effector T cells T CM central memory T cells (CD62L hi ) T EM effector memory T cells (CD62L lo ) T EMRA terminally differentiated CD45RA + effector memory T cells (human) T M memory T cells T MP memory-phenotype T cells (CD44 hi ) T N naïve T cells (CD44 lo ) T RM resident memory T cells (CD69/CD103-enriched) TCRtg T cell receptor transgenic TSLP Thymic stromal lymphopoietin