Roberts Natalie A, Adams Brian D, McCarthy Nicholas I, Tooze Reuben M, Parnell Sonia M, Anderson Graham, Kaech Susan M, Horsley Valerie
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520.
The Francis Crick Institute, London NW1 1AT, United Kingdom.
J Immunol. 2017 Aug 15;199(4):1250-1260. doi: 10.4049/jimmunol.1600941. Epub 2017 Jul 12.
Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice. Prdm1 is expressed by a subset of mouse TECs, and conditional deletion of in either or expressing cells in mice resulted in multisymptom autoimmune pathology. Notably, the development of Foxp3 regulatory T cells occurs normally in the absence of Blimp1. Importantly, nude mice developed anti-nuclear Abs when transplanted with null TECs, but not wild-type TECs, indicating that functions in TECs to regulate autoantibody production. We show that acts independently of Aire, a crucial transcription factor implicated in medullary TEC function. Collectively, our data highlight a previously unrecognized role for Prdm1 in regulating thymic epithelial function.
髓质胸腺上皮细胞（TECs）通过表达和呈递组织特异性抗原给发育中的胸腺细胞，很大程度上预防了自身免疫，从而导致自身反应性T细胞的缺失并支持调节性T细胞的发育。通过全基因组关联研究以及在小鼠中利用T细胞和树突状细胞中细胞类型特异性缺失该转录因子，已表明该转录因子与人类自身免疫性疾病有关。在本文中，我们证明Prdm1在TECs中发挥作用以预防小鼠自身免疫。Prdm1由一部分小鼠TECs表达，在小鼠的Prdm1或表达细胞中进行条件性缺失会导致多症状自身免疫病理。值得注意的是，在缺乏Blimp1的情况下，Foxp3调节性T细胞的发育正常发生。重要的是，裸鼠在移植Prdm1缺失的TECs而非野生型TECs时会产生抗核抗体，这表明Prdm1在TECs中发挥作用以调节自身抗体的产生。我们表明Prdm1的作用独立于Aire，Aire是一种与髓质TEC功能相关的关键转录因子。总体而言，我们的数据突出了Prdm1在调节胸腺上皮功能方面以前未被认识到的作用。
