MicroRNAs play an important role in the regulation of T cell development, activation, and differentiation. One of the most abundant microRNAs in lymphocytes is miR-181a, which controls T cell receptor (TCR) activation thresholds in thymic selection as well as in peripheral T cell responses. We previously found that miR-181a levels decline in T cells in the elderly. In this study, we identified TCF1 as a transcriptional regulator of pri-miR-181a. A decline in TCF1 levels in old individuals accounted for the reduced miR-181a expression impairing TCR signaling. Inhibition of GSK3ß restored expression of miR-181a by inducing TCF1 in T cells from old adults. GSK3ß inhibition enhanced TCR signaling to increase downstream expression of activation markers and production of IL-2. The effect involved the upregulation of miR-181a and the inhibition of DUSP6 expression. Thus, inhibition of GSK3ß can restore responses of old T cells by inducing miR-181a expression through TCF1.

MicroRNA在调节T细胞发育，激活和分化中起重要作用。淋巴细胞中最丰富的microRNA之一是miR-181a，它可控制胸腺选择以及周围T细胞反应中的T细胞受体（TCR）激活阈值。我们先前发现，老年人的T细胞中miR-181a水平下降。在这项研究中，我们确定了TCF1为pri-miR-181a的转录调节因子。老年个体TCF1水平下降是miR-181a表达降低的原因，这损害了TCR信号传导。抑制GSK3ß通过诱导老年人T细胞中的TCF1恢复了miR-181a的表达。GSK3ß抑制作用增强了TCR信号传导，从而增加了下游激活标记物的表达和IL-2的产生。该作用涉及miR-181a的上调和DUSP6表达的抑制。因此，抑制GSK3ß可以通过TCF1诱导miR-181a表达来恢复旧T细胞的应答。