Aire-expressing lymph node cells

自身免疫调节因子（Aire）基因突变可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蛋白的一个关键耐受原功能是促进胸腺髓上皮细胞（mTECs）外周自身抗原的异位表达。通过这种所谓的混杂基因表达，出乎意料地广谱的自身抗原在胸腺中被展示出来，用于中枢T细胞的耐受。在胸腺微环境之外，例如淋巴结中，Aire是否以及在哪里发挥类似的功能仍然存在争议。最近，在空气报告小鼠的研究中，在小鼠的淋巴结中发现了一种罕见的细胞类型，称为eTACs（胸腺外空气表达细胞）。这些eTACs表达Aire mRNA，有证据表明eTACs可能在外周耐受诱导中发挥作用。在初步工作中，我们现在已经在淋巴结中确定了第二种air -报告阳性细胞类型，其表型与eTACs明显不同。Aire- lncs（表达Aire的淋巴结细胞）似乎是一种新型的造血MHCⅱ类阳性抗原呈递细胞（APC）。重要的是，Aire蛋白在Aire- lncs中很容易检测到，而我们在eTACs中没有发现Aire蛋白。此外，我们已经获得证据表明Aire-LNCs以与mtec相似的方式表达外周抗原，初步结果表明Aire-LNCs参与外周耐受性的诱导。在目前的提案中，我们希望(i)澄清Aire-LNCs的细胞身份，（ii）表征Aire-LNCs中空气依赖的遗传程序，以及（iii）解决Aire-LNCs作为淋巴结中新型耐受性原性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.