During αβT cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3⁺ T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin β receptor (LTβR), we show that thymic tolerance mechanisms operate independently of LTβR-mediated mTEC development and organization. Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and support T-reg development despite loss of LTβR-mediated medulla organogenesis. Moreover, we demonstrate that LTβR controls thymic tolerance by regulating the frequency and makeup of intrathymic dendritic cells (DCs) required for effective thymocyte negative selection. In all, our study demonstrates that thymus medulla specialization for thymic tolerance segregates from medulla organogenesis and instead involves LTβR-mediated regulation of the thymic DC pool.

在 αβT 细胞发育过程中，胸腺髓质是 T 细胞耐受的重要微环境。这种功能专门化归因于其典型的组织拓扑结构，该拓扑结构由分支结构组成，其中包含髓质胸腺上皮细胞 (mTEC) 网络，以支持负选择和 Foxp3 ⁺ T 调节细胞 (T-reg) 发育。在这里，通过对胸腺髓质调节器淋巴毒素 β 受体 (LTβR) 进行 TEC 特异性删除，我们表明胸腺耐受机制的运作独立于 LTβR 介导的 mTEC 的发育和组织。与此一致的是，尽管 LTβR 介导的髓质器官发生丧失，mTEC 仍然继续表达 Fezf2 和 Aire（胸腺内自身抗原的调节因子）并支持 T-reg 发育。此外，我们证明LTβR通过调节有效胸腺细胞阴性选择所需的胸腺内树突状细胞（DC）的频率和组成来控制胸腺耐受性。总之，我们的研究表明，胸腺髓质对胸腺耐受的特化与髓质器官发生分离，而是涉及 LTβR 介导的胸腺 DC 库的调节。