Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC.
Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC.
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长非编码 RNA Lnc-Tim3 通过与 Tim-3 结合并诱导 HCC 中 Bat3 的核易位加剧 CD8 T 细胞耗竭
DOI：
10.1038/s41419-018-0528-7
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Sun B
中科院分区：
文献类型：
--
作者：
Ji J;Yin Y;Ju H;Xu X;Liu W;Fu Q;Hu J;Zhang X;Sun B
虽然长链非编码RNA（lncRNA）表达的第一个全面检查是在人CD 8 T淋巴细胞中进行的，但对它们在肝细胞癌（HCC）进展过程中在CD 8 T细胞功能中的作用知之甚少。在这里，我们发现Lnc-Tim 3在HCC患者的肿瘤浸润性CD 8 T细胞中上调并与IFN-γ和IL-2的产生负相关。Lnc-Tim 3在刺激CD 8 T耗竭和耗竭的CD 8 T细胞的存活中起关键作用。在机制上，Lnc-Tim 3特异性结合Tim-3并阻断其与Bat 3的相互作用，从而抑制下游Lck/NFAT 1/AP-1信号传导，导致Bat 3的核定位，并增强包括MDM 2和Bcl-2在内的抗凋亡基因的p300依赖性p53和RelA转录激活。总之，Lnc-Tim 3促进T细胞耗竭，这是一种与受损的抗肿瘤免疫相关的表型，表明Lnc-Tim 3及其相关的信号传导途径可能影响旨在调节获得性免疫系统的癌症治疗的结果。
Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc-Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/ NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system.
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影响因子：
64.5
作者：
Gomez JA;Wapinski OL;Yang YW;Bureau JF;Gopinath S;Monack DM;Chang HY;Brahic M;Kirkegaard K
通讯作者：
Kirkegaard K
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1007/978-3-0348-0837-8_16
发表时间：
2014-01-01
期刊：
INFLAMMATION AND CANCER
影响因子：
--
作者：
Bishayee, Anupam
通讯作者：
Bishayee, Anupam
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
82.9
作者：
Rangachari, Manu;Zhu, Chen;Sakuishi, Kaori;Xiao, Sheng;Karman, Jozsef;Chen, Andrew;Angin, Mathieu;Wakeham, Andrew;Greenfield, Edward A.;Sobel, Raymond A.;Okada, Hitoshi;McKinnon, Peter J.;Mak, Tak W.;Addo, Marylyn M.;Anderson, Ana C.;Kuchroo, Vijay K.
通讯作者：
Kuchroo, Vijay K.