肿瘤免疫微环境超级增强子

Nature | 全基因组分析揭示NR4A1作为T细胞功能失调的

2019-03-06  本文已影响44人  Florence_Super

Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

Abstract:

遭遇自身抗原或者暴露于肿瘤微环境后,T细胞会发生功能失调。T细胞的功能由共刺激信号调控。而dominance of negative co-stimulation 会导致T细胞功能的失调。然而,这其中的分子机制仍然不清楚。在本文中,利用小鼠体外耐受性T(tolerance T)细胞诱导系统和全基因组表观和基因表达测序发现,耐受性T细胞与效应性T和Treg细胞具有显著差异。其中,NR4A1在耐受性T细胞中稳定性高表达。NR4A1的过表达可以抑制效应细胞的功能,而delet 耐受性T细胞后,T细胞的耐受状态可以得到纠正,并增强了对抗肿瘤和慢性病毒感染的能力。在机制上,NR4A1 被招募结合于转录因子AP-1的结合位点从而通过抑制AP-1的功能抑制效应性基因的表达。NR4A1的结合也能够促进H3K27ac的乙酰化,从而导致耐受基因的表达。因此NR4A1可能能作为肿瘤免疫治疗的靶点。
 

Results:

利用之前作者已发表的小鼠体外模型获得耐受性T细胞。

Ttol cells exhibit distinct transcriptional and epigenetic features
 
基因座位可视化显示,在Ttol细胞中,谱系特异性效应因子(Ifng,Il4,Il17a)和转录因子(Tbx21,Gata3,Rorc)显示出低水平或H3K4me3和H3K27me3的缺失。相反,低反应相关基因(Egr3,Dgkz, Cdkn2a)以及衰竭相关基因(Lag3,Pdcd1,Tigit)显示出更高水平的H3K4me3。
Distribution of H3K4me3 and H3K27me3 peaks

体外模型构建:

In summary, our analysis indicates that the fate of naı¨ve T cells, as they encounter an antigen, is determined by not a single ‘second’ signal, but instead, rich combinatorial costi- mulation. In the absence of positive costimulation mediated by CD28 and ICOS pathways, negative costimula- tory molecules actively instruct T cells to develop into toler- ant T cells characterized by inactivation of intrinsic signaling and transcriptional programs. Tolerant Tcells expressed Grail but not transcription factors for effector T cells—T-bet and Eomes, as well as GATA-3 for CD4 T cells. On the other hand, during infection and inflammatory responses, B7 and B7h molecules are highly upregulated on APC, which overcomes the constitutive negative costimulation signals and results in a positive outcome of T-cell activation—extensive T-cell ex- pansion and generation of effector function. In this case, T cells express transcription factors T-bet, Eomes and GATA-3 but not Grail, Itch or cbl-b
T-cell tolerance or function is determined by combinatorial costimulatory signals

 

H3K27ac is a modification to DNA packaging protein Histone H3. It involves the acetylation at the 27th lysineresidue of the histone H3 protein. H3K27ac is associated with the higher activation of transcription and therefore defined as an active enhancer mark. H3K27ac is found at both proximal and distal regions of transcription start site (TSS). Since the H3K27ac and H3K27me3 modification is at the same location on the histone tail, they antagonize each other.[1] H3K27ac is often used to find active enhancers and poised enhancers subtracting from another enhancer mark H3K4me1 that contains all enhancers
from wikiwand

 

Summary

功能失调的T细胞中NR4A1表达上调,可能能作为免疫治疗的新靶点。


Integrated network analysis that identifies NR4A1-centred transcriptional modules
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