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，胸腺髓质代表了T细胞耐受的必要微环境。此功能专长归因于其典型的有组织拓扑结构，该拓扑结构由分支结构组成，该结构包含髓样胸腺上皮细胞（mTEC）网络以支持阴性选择和Foxp3 ⁺T调节细胞（T-reg）的发育。在这里，通过执行胸腺髓质调节因子淋巴毒素β受体（LTβR）的TEC特异性缺失，我们显示了胸腺耐受机制独立于LTβR介导的mTEC的发育和组织而发挥作用。与此相一致，尽管LTβR介导的髓质器官发生丧失，mTEC仍继续表达胸腺内自身抗原的调节剂Fezf2和Aire，并支持T-reg的发育。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，针对胸腺耐受性的胸腺髓质与髓质器官发生分离，而是涉及LTβR介导的胸腺DC池的调节。