Capone Alessia, Naro Chiara, Bianco Manuela, De Bardi Marco, Noël Floriane, Macchi Paolo, Battistini Luca, Soumelis Vassili, Volpe Elisabetta, Sette Claudio
Molecular Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
Department of Biology and Biotechnology Charles Darwin, Sapienza University, Rome, Italy.
iScience. 2021 Apr 30;24(5):102492. doi: 10.1016/j.isci.2021.102492. eCollection 2021 May 21.
T helper (Th) 17 cells protect from infections and are pathogenic in autoimmunity. While human Th17 cell differentiation has been defined, the global and stepwise transcriptional changes accompanying this process remain uncharacterized. Herein, by performing transcriptome analysis of human Th17 cells, we uncovered three time-regulated modules: early, involving exclusively "signaling pathways" genes; late, characterized by response to infections; and persistent, involving effector immune functions. To assign them an inflammatory or regulatory potential, we compared Th17 cells differentiated in presence or absence of interleukin (IL)-1β, respectively. Most inflammatory genes belong to the persistent module, whereas regulatory genes are lately or persistently induced. Among inflammatory genes, we identified the effector molecules IL17A, IL17F, IL26, IL6, interferon (IFN)G, IFNK, LTA, IL1A, platelet-derived growth factor (PDGF) A and the transcriptional regulators homeodomain-only protein homeobox (HOPX) and sex-determining-region-Y-box (SOX)2, whose expression was independently validated. This study provides an integrative representation of the stepwise human Th17 differentiation program and offers new perspectives toward therapeutic targeting of Th17-related autoimmune diseases.
辅助性T（Th）17细胞可抵御感染，但在自身免疫中具有致病性。虽然人类Th17细胞分化已被明确，但伴随这一过程的整体和逐步转录变化仍不清楚。在此，通过对人类Th17细胞进行转录组分析，我们发现了三个时间调控模块：早期，仅涉及“信号通路”基因；晚期，以对感染的反应为特征；持续性，涉及效应免疫功能。为了赋予它们炎症或调节潜能，我们分别比较了在存在或不存在白细胞介素（IL）-1β的情况下分化的Th17细胞。大多数炎症基因属于持续性模块，而调节基因是晚期或持续性诱导的。在炎症基因中，我们鉴定出效应分子IL17A、IL17F、IL26、IL6、干扰素（IFN）G、IFNK、LTA、IL1A、血小板衍生生长因子（PDGF）A以及转录调节因子仅含同源结构域的蛋白同源盒（HOPX）和性别决定区Y盒（SOX）2，其表达得到了独立验证。本研究提供了人类Th17分化程序逐步的综合表征，并为Th17相关自身免疫性疾病的治疗靶点提供了新的视角。
