Aire-expressing lymph node cells

自身免疫调节因子（Aire）基因突变导致自身免疫性多内分泌病-念珠菌病-外胚层营养不良（APECED），这是一种人类单基因遗传性自身免疫性疾病。Aire蛋白的一个重要致耐受性功能是促进外周自身抗原在胸腺髓质上皮细胞（mTEC）中的异位表达。通过这种所谓的混杂基因表达，在胸腺中展示了出乎意料的广谱自身抗原，用于中央T细胞耐受。Aire是否以及在胸腺微环境之外的何处发挥类似的功能仍然存在争议，例如在淋巴结中。最近，在Aire报告小鼠中的工作导致在小鼠的淋巴结中鉴定出一种罕见的细胞类型，即所谓的eTAC（胸腺外Aire表达细胞）。这些eTAC表达Aire mRNA，并且有证据表明eTAC可能在外周耐受诱导中起作用。在初步工作中，我们现在已经在淋巴结中鉴定了第二种Aire报告阳性细胞类型，其在表型上明显不同于eTAC。Aire-LNC（表达Aire的淋巴结细胞）似乎是一种新型的造血MHC II类阳性抗原呈递细胞（APC）。重要的是，Aire蛋白在Aire-LNC中很容易检测到，而我们在eTAC中找不到Aire蛋白。此外，我们已经获得的证据表明，Aire-LNC表达外周抗原以类似的方式作为mTECs，和初步结果表明，Aire-LNC参与外周耐受的诱导。在本提案中，我们希望（i）澄清Aire-LNC的细胞身份，（ii）表征Aire-LNC中的Aire-dependent遗传程序，以及（iii）解决Aire-LNC作为淋巴结中新型致耐受性APC的功能。

Mutations in the Autoimmune Regulator (Aire) gene result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenically inherited autoimmune disease in humans. A critical tolerogenic function of the Aire protein is to promote the ectopic expression of peripheral self-antigens in medullary thymic epithelial cells (mTECs). Through this so-called promiscuous gene expression, an unexpectedly broad spectrum of self-antigens is displayed in the thymus for central T cell tolerance. It remains controversial whether and where Aire might fulfill a similar function outside the thymic microenvironment, for instance in lymph nodes. Recently, work in Aire-reporter mice resulted in the identification of a rare cell-type, so-called eTACs (extrathymic Aire-expressing cells), in lymph nodes of the mouse. These eTACs express Aire mRNA and evidence was presented that eTACs might play a role in peripheral tolerance induction. In preliminary work, we have now identified a second Aire-reporter positive cell type in lymph nodes, which is phenotypically clearly distinct from eTACs. The Aire-LNCs (for Aire expressing lymph node cells) appear to be a novel type of hematopoietic MHC class II-positive antigen presenting cell (APC). Importantly, Aire protein is readily detectable in Aire-LNCs, whereas we could not find Aire protein in eTACs. Furthermore, we have obtained evidence indicating that Aire-LNCs express peripheral antigens in a similar manner as mTECs, and preliminary results suggest that Aire-LNCs are involved in the induction of peripheral tolerance. In the present proposal, we want to (i) clarify the cellular identity of Aire-LNCs, (ii) characterize the Aire-dependent genetic program in Aire-LNCs and (iii) address the function of Aire-LNCs as a novel type of tolerogenic APC in the lymph node.