Molecular mechanisms that regulate the formation of the thymic microenvironments

胸腺的髓质微环境通过自身反应性胸腺细胞的缺失和调节性T细胞的产生在自身耐受的建立中起着至关重要的作用。发育中的胸腺细胞和胸腺髓质上皮细胞（mTECs）之间的串扰或双向信号交换有助于胸腺髓质的形成。我们已经确定了介导胸腺串扰的分子。由阳性选择的胸腺细胞产生的肿瘤坏死因子超家族细胞因子，包括RANKL和α-光敏素，促进mTECs的增殖和分化。反过来，mTEC产生的CCR 7配体趋化因子促进阳性选择的胸腺细胞向髓质的迁移。发育中的胸腺细胞和mTECs之间的细胞因子串扰培育胸腺髓质的形成，从而调节自身耐受的建立。我们的研究结果还表明，XCL 1介导的胸腺树突状细胞的髓质积累有助于调节性T细胞的发育，并受到Aire的调节，并且胸腺蛋白酶体依赖性自身肽的产生是CD 8 + T细胞免疫活性库发育所必需的。

The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. We have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL and lymphotoxin, produced by positively selected thymocytes promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance. Our results also demonstrate that the XCL1-mediated medullary accumulation of thymic dendritic cells contributes to regulatory T cell development and is regulated by Aire and that thymoproteasome-dependent self-peptide production is required for the development of an immunocompetent repertoire of CD8+ T cells.