TOX is a critical regulator of tumour-specific T cell differentiation.
TOX is a critical regulator of tumour-specific T cell differentiation.
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DOI：
10.1038/s41586-019-1324-y
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发表时间：
2019-07
期刊：
影响因子：
64.8
通讯作者：
Schietinger A
中科院分区：
文献类型：
--
作者：
Scott AC;Dündar F;Zumbo P;Chandran SS;Klebanoff CA;Shakiba M;Trivedi P;Menocal L;Appleby H;Camara S;Zamarin D;Walther T;Snyder A;Femia MR;Comen EA;Wen HY;Hellmann MD;Anandasabapathy N;Liu Y;Altorki NK;Lauer P;Levy O;Glickman MS;Kaye J;Betel D;Philip M;Schietinger A
肿瘤特异性CD 8 T细胞功能障碍是一种分化状态，与功能性效应或记忆T细胞状态不同。在这里，我们确定核因子TOX作为肿瘤特异性T（TST）细胞分化的重要调节因子。我们表明，TOX是高度表达在功能失调的TST细胞从肿瘤和疲惫的T细胞在慢性病毒感染。TOX的表达由慢性T细胞受体刺激和NFAT活化驱动。TOX在体外效应T细胞中的异位表达诱导了与T细胞耗竭相关的转录程序。相反，肿瘤中TST细胞中Tox的缺失废除了耗竭程序：Tox缺失的TST细胞没有上调抑制性受体（如Pdcd 1，Entpd 1，Havcr 2，Cd 244和Tigit）的基因，其染色质在很大程度上仍然不可接近，并保留了转录因子如TCF-1的高表达。尽管其正常的，“非耗尽”的免疫表型，毒素删除的TST细胞仍然功能失调，这表明抑制性受体的表达的调节是解耦的效应功能的丧失。值得注意的是，尽管Tox缺失的CD 8 T细胞在急性感染时正常分化为效应和记忆状态，但Tox缺失的TST细胞未能在肿瘤中持续存在。我们假设，在慢性抗原刺激（如癌症）的情况下，TOX诱导的耗竭程序有助于防止T细胞的过度刺激和活化诱导的细胞死亡。
Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
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影响因子：
4.4
作者：
O'Flaherty E;Kaye J
通讯作者：
Kaye J
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
3.7
作者：
Espinosa-Carrasco G;Villard M;Le Saout C;Louis-Plence P;Vicente R;Hernandez J
通讯作者：
Hernandez J
影响因子：
64.8
作者：
JAIN, JN;MCCAFFREY, PG;RAO, A
通讯作者：
RAO, A
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.