Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus
Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus
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DOI：
10.1038/nature03886
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发表时间：
2005-08-25
期刊：
影响因子：
64.8
通讯作者：
Liu, YJ
中科院分区：
文献类型：
--
作者：
Watanabe, N;Wang, YH;Liu, YJ
哈塞尔小体-150多年前首次在人类胸腺中被描述（1）-是胸腺髓质内的上皮细胞群。这些结构的物理性质在哺乳动物物种之间存在差异（2）。虽然Hassall小体被认为在胸腺内清除凋亡胸腺细胞（3，4）和促进发育中胸腺细胞成熟（5）中起作用，但Hassall小体的功能仍然是一个谜。在这里，我们报告，人类哈氏小体表达胸腺基质淋巴细胞生成素（TSLP）。人TSLP激活胸腺CD 11 c阳性树突状细胞以表达高水平的CD 80和CD 86。然后，这些TSLP条件树突状细胞能够诱导CD 4（+）CD 8（-）CD 25（-）胸腺T细胞增殖和分化为CD 4（+）CD 25（+）FOXP 3（+）（叉头框P3）调节性T细胞。这种诱导依赖于肽-主要组织相容性复合物II类相互作用，以及CD 80和CD 86以及白细胞介素2的存在。免疫组织化学研究表明，CD 25（+）CTLA 4（+）（细胞毒性T淋巴细胞相关蛋白4）调节性T细胞在胸腺髓质中与活化或成熟的树突状细胞和表达TSLP的Hassall小体相关。这些发现表明，Hassall小体在树突状细胞介导的中等至高亲和力自身反应性T细胞的二次阳性选择中具有关键作用，导致胸腺内CD 4（+）CD 25（+）调节性T细胞的产生。
Hassall's corpuscles - first described in the human thymus over 150 years ago(1) - are groups of epithelial cells within the thymic medulla. The physical nature of these structures differs between mammalian species(2). Although Hassall's corpuscles have been proposed to act in both the removal of apoptotic thymocytes(3,4) and the maturation of developing thymocytes(5) within the thymus, the function of Hassall's corpuscles has remained an enigma. Here we report that human Hassall's corpuscles express thymic stromal lymphopoietin ( TSLP). Human TSLP activates thymic CD11c-positive dendritic cells to express high levels of CD80 and CD86. These TSLP-conditioned dendritic cells are then able to induce the proliferation and differentiation of CD4(+) CD8(-) CD25(-) thymic T cells into CD4(+) CD25(+) FOXP3(+) (forkhead box P3) regulatory T cells. This induction depends on peptide - major histocompatibility complex class II interactions, and the presence of CD80 and CD86, as well as interleukin 2. Immunohistochemistry studies reveal that CD25(+) CTLA4(+) (cytotoxic T-lymphocyte-associated protein 4) regulatory T cells associate in the thymic medulla with activated or mature dendritic cells and TSLP-expressing Hassall's corpuscles. These findings suggest that Hassall's corpuscles have a critical role in dendritic-cell-mediated secondary positive selection of medium-to-high affinity self-reactive T cells, leading to the generation of CD4(+) CD25(+) regulatory T cells within the thymus.