Decline in miR-181a Expression With Age Impairs T Cell Receptor Sensitivity by Increasing DUSP6 Activity

Nat Med. 2012 Oct;18(10):1518-24. doi: 10.1038/nm.2963. Epub 2012 Sep 30.

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 ζ 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cyclohexylamines / pharmacology
  • Dual Specificity Phosphatase 6 / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Indenes / pharmacology
  • Lymphocyte Activation
  • MAP Kinase Signaling System
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Phosphorylation
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

  • 2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one
  • Cyclohexylamines
  • Indenes
  • MIRN142 microRNA, human
  • MIrn181 microRNA, human
  • MicroRNAs
  • Receptors, Antigen, T-Cell
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6