Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling

Won Woo Lee, Dapeng Cui, Marta Czesnikiewicz-Guzik, Ricardo Z.N. Vencio, Ilya Shmulevich, Alan Aderem, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1001-1011
Number of pages11
JournalRejuvenation Research
Volume11
Issue number6
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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