Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Sci Immunol. 2021 Nov 12;6(65):eabl5053. doi: 10.1126/sciimmunol.abl5053.
The autoimmune regulator (Aire), a well-defined transcriptional regulator in the thymus, is also found in extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. eTACs are hematopoietic antigen-presenting cells and inducers of immune tolerance, but their precise identity has remained unclear. Here, we use single-cell multiomics, transgenic murine models, and functional approaches to define eTACs at the transcriptional, genomic, and proteomic level. We find that eTACs consist of two similar cell types: CCR7 Aire-expressing migratory dendritic cells (AmDCs) and an Aire population coexpressing Aire and retinoic acid receptor–related orphan receptor γt (RORγt) that we term Janus cells (JCs). Both JCs and AmDCs have the highest transcriptional and genomic homology to CCR7 migratory dendritic cells. eTACs, particularly JCs, have highly accessible chromatin and broad gene expression, including a range of tissue-specific antigens, as well as remarkable homology to medullary thymic epithelium and RANK-dependent Aire expression. Transgenic self-antigen expression by eTACs is sufficient to induce negative selection and prevent autoimmune diabetes. This transcriptional, genomic, and functional symmetry between eTACs (both JCs and AmDCs) and medullary thymic epithelium—the other principal Aire-expressing population and a key regulator of central tolerance—identifies a core program that may influence self-representation and tolerance across the spectrum of immune development.
自身免疫调节因子（Aire）是胸腺中一种明确的转录调节因子，也存在于次级淋巴器官中的表达 Aire 的胸腺外 Aire 表达细胞（eTAC）中。eTAC 是造血抗原呈递细胞和免疫耐受诱导剂，但它们的确切身份仍不清楚。在这里，我们使用单细胞多组学、转基因小鼠模型和功能方法，在转录组、基因组和蛋白质组水平上定义 eTAC。我们发现 eTAC 由两种相似的细胞类型组成：CCR7 Aire 表达的迁移树突状细胞（AmDC）和一种同时表达 Aire 和维甲酸受体相关孤儿受体γt（RORγt）的 Aire 群体，我们称之为双生子细胞（JCs）。JC 和 AmDC 在转录组和基因组上与 CCR7 迁移树突状细胞的同源性最高。eTAC，特别是 JCs，具有高度可及的染色质和广泛的基因表达，包括一系列组织特异性抗原，以及与骨髓胸腺上皮和 RANK 依赖性 Aire 表达的显著同源性。eTAC（包括 JCs 和 AmDC）和骨髓胸腺上皮之间的这种转录组、基因组和功能对称性——另一个主要的 Aire 表达群体和中央耐受的关键调节剂——确定了一个核心程序，该程序可能会影响自身表现和整个免疫发育过程中的耐受。
