Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands ; Groningen Research Initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
PLoS One. 2013 Oct 1;8(10):e76217. doi: 10.1371/journal.pone.0076217. eCollection 2013.
Immune cell-type specific miRNA expression patterns have been described but the detailed role of single miRNAs in the function of T-cells remains largely unknown. We investigated the role of miR-21 in the function of primary human CD4+ T-cells. MiR-21 is substantially expressed in T-cells with a memory phenotype, and is robustly upregulated upon αCD3/CD28 activation of both naive and memory T-cells. By inhibiting the endogenous miR-21 function in activated naive and memory T-cells, we showed that miR-21 regulates fundamentally different aspects of T-cell biology, depending on the differentiation status of the T-cell. Stable inhibition of miR-21 function in activated memory T-cells led to growth disadvantage and apoptosis, indicating that the survival of memory T-cells depends on miR-21 function. In contrast, stable inhibition of miR-21 function in activated naive T-cells did not result in growth disadvantage, but led to a significant induction of CCR7 protein expression. Direct interaction between CCR7 and miR-21 was confirmed in a dual luciferase reporter assay. Our data provide evidence for a dual role of miR-21 in CD4+ T cells; Regulation of T-cell survival is confined to activated memory T-cells, while modulation of potential homing properties, through downregulation of CCR7 protein expression, is observed in activated naive T-cells.
免疫细胞类型特异性 miRNA 表达模式已被描述，但单个 miRNA 在 T 细胞功能中的详细作用在很大程度上仍然未知。我们研究了 miR-21 在原代人 CD4+ T 细胞功能中的作用。miR-21 在具有记忆表型的 T 细胞中大量表达，并在 αCD3/CD28 激活幼稚和记忆 T 细胞时强烈上调。通过抑制激活的幼稚和记忆 T 细胞内源性 miR-21 的功能，我们表明 miR-21 根据 T 细胞的分化状态调节 T 细胞生物学的完全不同方面。稳定抑制激活的记忆 T 细胞中的 miR-21 功能会导致生长劣势和细胞凋亡，表明记忆 T 细胞的存活依赖于 miR-21 的功能。相比之下，稳定抑制激活的幼稚 T 细胞中的 miR-21 功能不会导致生长劣势，但会导致 CCR7 蛋白表达的显著诱导。在双荧光素酶报告基因测定中证实了 CCR7 和 miR-21 之间的直接相互作用。我们的数据为 miR-21 在 CD4+ T 细胞中的双重作用提供了证据；调节 T 细胞存活仅限于激活的记忆 T 细胞，而通过下调 CCR7 蛋白表达调节潜在的归巢特性，则在激活的幼稚 T 细胞中观察到。
