An IRF1-IRF4 Toggle-Switch Controls Tolerogenic and Immunogenic Transcriptional Programming in Human Langerhans Cells.
An IRF1-IRF4 Toggle-Switch Controls Tolerogenic and Immunogenic Transcriptional Programming in Human Langerhans Cells.
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DOI：
10.3389/fimmu.2021.665312
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发表时间：
2021
影响因子：
7.3
通讯作者：
Polak ME
中科院分区：
文献类型：
--
作者：
Davies J;Vallejo AF;Sirvent S;Porter G;Clayton K;Qumbelo Y;Stumpf P;West J;Gray CM;Chigorimbo-Murefu NTL;MacArthur B;Polak ME
朗格汉斯细胞（LC）作为免疫系统哨兵的密集网络存在于表皮中，协调免疫原性和致耐受性免疫应答。为了确定指导诱导LC免疫激活的分子开关，我们对通过暴露于TNF-α（皮肤产生的关键促炎信号）的LC的单细胞RNA测序鉴定的基因调控网络进行了数学建模。我们的方法描绘了LC表型激活的三个程序（免疫原性，致耐受性或矛盾），并证实TNF-α增强LC免疫原性编程。通过调节子分析和互信息建模，我们确定了IRF 1是调节LC免疫原性的关键转录因子。应用数学切换开关模型，耦合IRF 1与耐受性诱导转录因子，确定了调节耐受性和免疫原性之间切换的关键转录因子集，并正确预测了来自不同身体部位的LC中的LC行为。我们的研究结果提供了一个机制解释不同的转录因子之间的组合相互作用如何协调特定的转录程序在人类LC，解释局部组织微环境的微环境背景。
Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF-alpha, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF-alpha enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.
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影响因子：
7.3
作者：
Clayton K;Vallejo AF;Davies J;Sirvent S;Polak ME
通讯作者：
Polak ME
影响因子：
12.3
作者：
Lun AT;Bach K;Marioni JC
通讯作者：
Marioni JC
影响因子：
20.3
作者：
Banchereau, Jacques;Thompson-Snipes, Luann;Klechevsky, Eynav
通讯作者：
Klechevsky, Eynav
影响因子：
8
作者：
Gray, Clive M.;O'Hagan, Kyle L.;Hope, Thomas J.
通讯作者：
Hope, Thomas J.
影响因子：
6.4
作者：
Cumberbatch, M;Dearman, RJ;Kimber, I
通讯作者：
Kimber, I