Villaseñor Jennifer, Besse Whitney, Benoist Christophe, Mathis Diane
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15854-9. doi: 10.1073/pnas.0808069105. Epub 2008 Oct 3.
Thymic medullary epithelial cells (MECs) express a broad repertoire of peripheral-tissue antigens (PTAs), many of which depend on the transcriptional regulatory factor Aire. Although Aire is known to be critically important for shaping a self-tolerant T cell repertoire, its role in MEC maturation and function remains poorly understood. Using a highly sensitive and reproducible single-cell PCR assay, we demonstrate that individual Aire-expressing MECs transcribe a subset of PTA genes in a probabilistic fashion, with no signs of preferential coexpression of genes characteristic of particular extrathymic epithelial cell lineages. In addition, Aire-dependent PTA genes in MECs are transcribed monoallelically or biallelically in a stochastic pattern, in contrast to the usually biallelic transcription of these same genes in the relevant peripheral cells or of Aire-independent genes in MECs. Expression of PTA genes in MECs depends on transcriptional regulators and uses transcriptional start sites different from those used in peripheral cells. These findings support the "terminal differentiation" model of Aire function: as MECs mature, they transcribe more and more PTA genes, culminating in a cell population that is both capable of presenting antigens (MHCII(hi), CD80(hi)) and can draw on a large repertoire of antigens to present.
胸腺髓质上皮细胞（MECs）表达多种外周组织抗原（PTAs），其中许多抗原依赖于转录调节因子Aire。尽管已知Aire对于塑造自我耐受的T细胞库至关重要，但其在MEC成熟和功能中的作用仍知之甚少。我们使用一种高度灵敏且可重复的单细胞PCR检测方法，证明单个表达Aire的MEC以概率方式转录一部分PTA基因，没有迹象表明特定胸腺外上皮细胞谱系特征性基因存在优先共表达。此外，与这些相同基因在相关外周细胞中通常的双等位基因转录或MEC中不依赖Aire的基因转录不同，MEC中依赖Aire的PTA基因以随机模式单等位基因或双等位基因转录。MEC中PTA基因的表达取决于转录调节因子，并使用与外周细胞不同的转录起始位点。这些发现支持了Aire功能的“终末分化”模型：随着MEC成熟，它们转录越来越多的PTA基因，最终形成一个既能呈递抗原（MHCII(高)，CD80(高)）又能利用大量抗原库进行呈递的细胞群体。
