Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV.
Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV.
复制标题
DOI：
10.3389/fimmu.2021.601298
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Yao ZQ
中科院分区：
文献类型：
--
作者：
Nguyen LNT;Nguyen LN;Zhao J;Schank M;Dang X;Cao D;Khanal S;Chand Thakuri BK;Lu Z;Zhang J;Li Z;Morrison ZD;Wu XY;El Gazzar M;Ning S;Wang L;Moorman JP;Yao ZQ
T细胞对于控制病毒感染至关重要，并且T细胞应答由非编码RNA的动态网络调节，包括microRNA（miR）和长非编码RNA（lncRNA）。在这里，我们表明，激活诱导的lncRNA生长抑制特异性转录本5（GAS 5）的下降激活DNA损伤反应（DDR），并通过上调miR-21调节来自HIV感染者（PLHIV）的CD 4 T细胞的细胞功能和凋亡。值得注意的是，在接受抗逆转录病毒治疗（ART）的PLHIV中观察到GAS 5-miR 21介导的DDR和T细胞功能障碍，尽管病毒学控制良好，但由于低度炎症，这些人经常表现出免疫激活。我们发现GAS 5负调控miR-21的表达，进而控制参与DNA损伤和细胞反应的关键信号通路。T细胞的持续刺激降低了GAS 5，增加了miR-21，结果导致CD 4 T细胞的功能障碍和凋亡。重要的是，ART控制的PLHIV和健康受试者（HS）中这种炎症驱动的T细胞过度活化和异常凋亡可以通过拮抗GAS 5-miR-21轴来逆转。此外，与野生型GAS 5转录物相比，GAS 5基因外显子4上的miR-21结合位点突变以产生GAS 5突变体消除了其调节miR-21表达以及T细胞活化和凋亡标志物的能力。我们的数据表明，在HIV感染期间，GAS 5通过miR-21介导的信号传导调节TCR介导的CD 4 T细胞活化和凋亡。然而，在HIV感染期间，GAS 5对T细胞耗竭的作用可能是由GAS 5-miR-21介导的信号传导以外的机制介导的。这些结果表明，靶向GAS 5-miR-21轴可以改善ART治疗的PLHIV中CD 4 T细胞的活性和寿命。这种方法也可以用于靶向与T细胞过度活化、衰竭和过早免疫老化相关的其他感染性或炎性疾病。
T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.
登录
查看更多内容
DOI：
10.4049/jimmunol.1101235
发表时间：
2011-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lu TX;Hartner J;Lim EJ;Fabry V;Mingler MK;Cole ET;Orkin SH;Aronow BJ;Rothenberg ME
通讯作者：
Rothenberg ME
影响因子：
15.9
作者：
De Paoli, P;Zanussi, S;Tirelli, U
通讯作者：
Tirelli, U
影响因子：
8.8
作者：
Kim, Chulwoo;Hu, Bin;Goronzy, Jorg J.
通讯作者：
Goronzy, Jorg J.
影响因子：
9.1
作者：
D'Amico, R;Yang, YJ;Jacobson, MA
通讯作者：
Jacobson, MA
影响因子：
7.3
作者：
Cao D;Khanal S;Wang L;Li Z;Zhao J;Nguyen LN;Nguyen LNT;Dang X;Schank M;Thakuri BKC;Zhang J;Lu Z;Wu XY;Morrison ZD;El Gazzar M;Ning S;Moorman JP;Yao ZQ
通讯作者：
Yao ZQ