Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan.
Cell Rep. 2022 Feb 15;38(7):110384. doi: 10.1016/j.celrep.2022.110384.
Impaired production of thymic regulatory T cells (Tregs) is implicated in the development of Aire-dependent autoimmunity. Because Tregs require agonistic T cell receptor stimuli by self-antigens to develop, reduced expression of self-antigens from medullary thymic epithelial cells (mTECs) has been considered to play a major role in the reduced Treg production in Aire deficiency. Here, we show that mTECs abnormally express co-inhibitory receptor CTLA-4 if Aire is non-functional. Upon binding with CD80/CD86 ligands expressed on thymic dendritic cells (DCs), the ectopically expressed CTLA-4 from Aire-deficient mTECs removes the CD80/CD86 ligands from the DCs. This attenuates the ability of DCs to provide co-stimulatory signals and to present self-antigens transferred from mTECs, both of which are required for Treg production. Accordingly, impaired production of Tregs and organ-specific autoimmunity in Aire-deficient mice are rescued by the depletion of CTLA-4 expression from mTECs. Our studies illuminate the significance of mTEC-DC interaction coordinated by Aire for the establishment of thymic tolerance.
胸腺调节性 T 细胞（Tregs）的产生受损与 Aire 依赖性自身免疫的发展有关。由于 Tregs 的发育需要自身抗原的激动性 T 细胞受体刺激，因此，认为来自髓质胸腺上皮细胞（mTEC）的自身抗原表达减少在 Aire 缺乏时 Treg 产生减少中起主要作用。在这里，我们表明，如果 Aire 无功能，mTEC 会异常表达共抑制受体 CTLA-4。与表达在胸腺树突状细胞（DC）上的 CD80/CD86 配体结合后，来自 Aire 缺陷 mTEC 的异位表达 CTLA-4 会从 DC 上除去 CD80/CD86 配体。这会削弱 DC 提供共刺激信号和呈递从 mTEC 转移而来的自身抗原的能力，这两者都是 Treg 产生所必需的。因此，通过从 mTEC 中耗尽 CTLA-4 的表达，可挽救 Aire 缺陷小鼠中 Treg 的产生受损和器官特异性自身免疫。我们的研究阐明了 Aire 协调的 mTEC-DC 相互作用对建立胸腺耐受的重要性。
