title: Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity.
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.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Li
authors.forename: Mingcan
authors.initials: M
authors.lastname: Yu
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Tsang
authors.forename: Eswar
authors.initials: E
authors.lastname: Krishnan
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; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003514:Cyclohexylamines / Q000494:pharmacology; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: C543522:2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one; D003514:Cyclohexylamines; D007192:Indenes; C555159:MIRN142 microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6