Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Front Immunol. 2021 Jun 15;12:665312. doi: 10.3389/fimmu.2021.665312. eCollection 2021.
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.
郎格汉斯细胞 (LCs) 作为免疫系统的密集网络存在于表皮中，协调免疫原性和耐受性免疫反应。为了确定指导 LC 免疫激活诱导的分子开关，我们对 TNF-α 暴露的 LCs 的单细胞 RNA 测序鉴定的基因调控网络进行了数学建模，TNF-α 是皮肤产生的关键促炎信号。我们的方法描绘了 LC 表型激活的三个程序（免疫原性、耐受性或模棱两可），并证实 TNF-α 增强了 LC 的免疫原性编程。通过调控子分析和互信息建模，我们确定 IRF1 是调节 LC 免疫原性的关键转录因子。应用数学拨动开关模型，将 IRF1 与诱导耐受的转录因子耦合，确定了调节耐受性和免疫原性之间转换的关键转录因子集，并正确预测了来自不同身体部位的 LCs 中的 LC 行为。我们的研究结果提供了一种机制解释，说明不同转录因子之间的组合相互作用如何在人类 LCs 中协调特定的转录程序，解释了局部组织微环境的微环境上下文。
