title: Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling.
abstract: The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naïve CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naïve CD4 T cells with age.
authors.affiliation: Kathleen B and Mason I Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.forename: Dapeng
authors.initials: D
authors.lastname: Cui
authors.forename: Marta
authors.initials: M
authors.lastname: Czesnikiewicz-Guzik
authors.forename: Ricardo Z N
authors.initials: RZ
authors.lastname: Vencio
authors.forename: Ilya
authors.initials: I
authors.lastname: Shmulevich
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015032:Zinc / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D008668:Metallothionein; D015032:Zinc