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

作者：Li Guangjin; Yu Mingcan; Lee Won Woo; Tsang Michael; Krishnan Eswar; Weyand Cornelia M; Goronzy Joerg J^*

来源：Nature Medicine, 2012, 18(10): 1518-U113.

DOI：10.1038/nm.2963

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-gamma 1 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.

• 出版日期2012-10