Lonardi Silvia, Bianchetto-Aguilera Francisco Ma, Monti Matilde, Di Matteo Anna, Missale Francesco, Picinoli Sara, Bugatti Mattia, Benedetti Martina, Ferrari Giorgia, Cassatella Marco A, Moratto Daniele, Zini Stefania, Agostini Valentina, Savoldi Viola, Lorenzi Luisa, Chiarini Marco, Facchetti Fabio, Wu Shitong, Antonova Alina Ulezko, Liu Yizhou A, Cella Marina, Ghigna Claudia, Colonna Marco, Vermi William
Pathology Section, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
General Pathology Section, Department of Medicine, University of Verona, Verona, Italy.
Front Immunol. 2025 May 30;16:1527499. doi: 10.3389/fimmu.2025.1527499. eCollection 2025.
The retinoic-acid-receptor-related orphan receptor gamma t (RORγt) isoform is required for the development of lymphoid organs, T-helper 17 cells (Th17), and innate lymphoid cells (ILC3s). Recent data in mouse and human have revealed non-T, non-ILC3 cell populations with antigen presenting features that express RORγt. This study maps the presence of RORγt cells with dendritic cell (DC) features in human adult and fetal lymphoid tissues.
By combining multicolor flow cytometry, RNAseq of peripheral blood cells, analysis of lymph node scRNAseq datasets, and microscopic analysis on human tissue sections and single-cell suspensions, this study maps the presence of RORγt cells with DC features in human tissues.
RORγt-DCs are found in human lymphoid organs, particularly in lymph nodes. Lymph node RORγt-DCs are located in the interfollicular area surrounding high endothelial venules and in the marginal sinuses. In terms of phenotype, RORγt-DCs are distinct from other nodal dendritic cells. They express PRDM16 and PIGR as well as transcripts supporting the antigen presentation machinery, while lacking stromal markers. A significant fraction of RORγt-DCs is proliferating, suggesting local self-renewal. Moreover, most of them lack autoimmune regulator (AIRE) expression. Comparison with mouse RORγt Thetis cells (TC) and Janus cells (JC) shows more similarity with group II TC than group I and III TC or JC, all of which are tolerogenic and express AIRE.
Overall, this study identifies human lymph nodes as a relevant niche for RORγt-DCs and establishes tools for their microscopic mapping in human disease states.
维甲酸受体相关孤儿受体γt（RORγt）亚型对于淋巴器官、辅助性T细胞17（Th17）和固有淋巴细胞（ILC3s）的发育是必需的。最近在小鼠和人类中的数据揭示了具有抗原呈递特征且表达RORγt的非T、非ILC3细胞群体。本研究描绘了在成人和胎儿淋巴组织中具有树突状细胞（DC）特征的RORγt细胞的存在情况。
通过结合多色流式细胞术、外周血细胞的RNA测序、淋巴结单细胞RNA测序数据集的分析以及对人体组织切片和单细胞悬液的显微镜分析，本研究描绘了人体组织中具有DC特征的RORγt细胞的存在情况。
在人类淋巴器官中发现了RORγt-DC，尤其是在淋巴结中。淋巴结RORγt-DC位于高内皮静脉周围的滤泡间区和边缘窦中。就表型而言，RORγt-DC与其他淋巴结树突状细胞不同。它们表达PRDM16和PIGR以及支持抗原呈递机制的转录本，同时缺乏基质标志物。相当一部分RORγt-DC正在增殖，表明其具有局部自我更新能力。此外，它们中的大多数缺乏自身免疫调节因子（AIRE）的表达。与小鼠RORγt西蒂斯细胞（TC）和雅努斯细胞（JC）的比较表明，与I组和III组TC或JC相比，其与II组TC更相似，而I组和III组TC以及JC均具有耐受性且表达AIRE。
总体而言，本研究确定人类淋巴结是RORγt-DC的一个相关微环境，并建立了在人类疾病状态下对其进行微观定位的工具。
