Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity

Guangjin Li, Mingcan Yu, Won Woo Lee, Michael Tsang, Eswar Krishnan, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

212 Scopus citations

Abstract

The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4+ T cells, whereas other signals, such as z chain-associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden- 1-one improved CD4+ T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.

Original languageEnglish (US)
Pages (from-to)1518-1524
Number of pages7
JournalNature Medicine
Volume18
Issue number10
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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