TY - JOUR
T1 - Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling
AU - Lee, Won Woo
AU - Cui, Dapeng
AU - Czesnikiewicz-Guzik, Marta
AU - Vencio, Ricardo Z.N.
AU - Shmulevich, Ilya
AU - Aderem, Alan
AU - Weyand, Cornelia M.
AU - Goronzy, Jörg J.
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=58149236973&partnerID=8YFLogxK
U2 - 10.1089/rej.2008.0747
DO - 10.1089/rej.2008.0747
M3 - Article
C2 - 19072254
AN - SCOPUS:58149236973
SN - 1549-1684
VL - 11
SP - 1001
EP - 1011
JO - Rejuvenation Research
JF - Rejuvenation Research
IS - 6
ER -