Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity.
Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity.
复制标题
作者：
人类免疫系统对疫苗接种的反应能力随着年龄的增长而下降。我们发现在T细胞受体(Tcr)诱导的初始CD_4+T细胞ERK磷酸化中存在与年龄相关的缺陷(P<；0.0001)，而其他信号，如ZAP70和PLC-γ1的磷酸化并未受到损害。由于miR-181a抑制作用减弱(r=−0.59，P<；0.0001)，导致双特异性磷酸酶6的蛋白水平随年龄增加而增加(r=0.68，P<；0.0001)。MiR-181a的重建降低了老年人幼稚CD4+T细胞中DUSP6的水平。用miR-181a或特定的siRNA抑制DUSP6，以及用变构抑制剂(E)-2-benzylidene-3-(cyclohexylamino)-2，3-dihydro-1H-inden-1-one抑制DUSP6可以改善CD_4~+T细胞的反应，表现为激活标志物的表达增加，促进了增殖，并支持优先的Th1分化。DUSP6是恢复老年人T细胞反应的潜在干预靶点，可能会增强疫苗接种的有效性。
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 ERK phosphorylation in naïve CD4+ T cells (P<0.0001) while other signals, such as ZAP70 and PLC-γ1 phosphorylation were not impaired. The defective ERK signaling was caused by the dual specific phosphatase (DUSP) 6 whose protein levels increased with age (r = 0.68, P < 0.0001) due to a decline in repression by miR-181a (r = −0.59, P < 0.0001). Reconstitution of miR-181a lowered DUSP6 levels in naïve CD4+ T cells in elderly individuals. DUSP6 repression with miR-181a or specific siRNA, and DUSP6 inhibition with 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 TH1 differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.
登录
查看更多内容
影响因子：
15.3
作者：
Macallan, DC;Wallace, D;Zhang, Y;de Lara, C;Worth, AT;Ghattas, H;Griffin, GE;Beverley, PCL;Tough, DE
通讯作者：
Tough, DE
DOI：
10.1186/1742-4933-4-9
发表时间：
2007-12-11
期刊：
Immunity & ageing : I & A
影响因子：
--
作者：
Aspinall, Richard;Del Giudice, Giuseppe;Sambhara, Suryaprakash
通讯作者：
Sambhara, Suryaprakash
影响因子：
2.6
作者：
Lee WW;Cui D;Czesnikiewicz-Guzik M;Vencio RZ;Shmulevich I;Aderem A;Weyand CM;Goronzy JJ
通讯作者：
Goronzy JJ
影响因子：
5.5
作者：
Couch, Robert B.;Winokur, Patricia;Ruben, Frederick L.
通讯作者：
Ruben, Frederick L.
DOI：
10.1073/pnas.0813390106
发表时间：
2009-03-10
影响因子：
11.1
作者：
Galli, Grazia;Medini, Duccio;Castellino, Flora
通讯作者：
Castellino, Flora