Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany.
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Immunity. 2015 Jun 16;42(6):1048-61. doi: 10.1016/j.immuni.2015.05.013. Epub 2015 Jun 9.
Thymic antigen-presenting cells (APCs) such as dendritic cells and medullary thymic epithelial cells (mTECs) use distinct strategies of self-antigen expression and presentation to mediate central tolerance. The thymus also harbors B cells; whether they also display unique tolerogenic features and how they genealogically relate to peripheral B cells is unclear. Here, we found that Aire is expressed in thymic but not peripheral B cells. Aire expression in thymic B cells coincided with major histocompatibility class II (MHCII) and CD80 upregulation and immunoglobulin class-switching. These features were recapitulated upon immigration of naive peripheral B cells into the thymus, whereby this intrathymic licensing required CD40 signaling in the context of cognate interactions with autoreactive CD4(+) thymocytes. Moreover, a licensing-dependent neo-antigen selectively upregulated in immigrating B cells mediated negative selection through direct presentation. Thus, autoreactivity within the nascent T cell repertoire fuels a feed forward loop that endows thymic B cells with tolerogenic features.
胸腺抗原呈递细胞（APCs），如树突状细胞和髓质胸腺上皮细胞（mTECs），使用不同的自身抗原表达和呈递策略来介导中枢耐受。胸腺还含有 B 细胞；它们是否也表现出独特的耐受特征以及它们与外周 B 细胞在谱系上的关系尚不清楚。在这里，我们发现 Aire 在胸腺 B 细胞中表达，而不在外周 B 细胞中表达。胸腺 B 细胞中 Aire 的表达与主要组织相容性复合体 II（MHCII）和 CD80 的上调以及免疫球蛋白类转换同时发生。这些特征在幼稚的外周 B 细胞进入胸腺时被重现，其中这种胸腺内许可需要在与自身反应性 CD4(+) 胸腺细胞的同源相互作用的背景下 CD40 信号传导。此外，选择性上调的许可依赖性新抗原通过直接呈递介导负选择。因此，在新生 T 细胞库中的自身反应性为赋予胸腺 B 细胞耐受特征提供了正反馈回路。
