Opposing chemokine gradients control human thymocyte migration in situ
Opposing chemokine gradients control human thymocyte migration in situ
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DOI：
10.1172/jci67175
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
Robey, Ellen A.
中科院分区：
文献类型：
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作者：
Halkias, Joanna;Melichar, Heather J.;Robey, Ellen A.
胸腺细胞从皮质到髓质的有序迁移对于适当选择成熟T细胞库是至关重要的。大多数胸腺细胞迁移的研究依赖于小鼠模型，但我们对人类胸腺细胞如何在胸腺中找到合适的解剖位置知之甚少。此外，在小鼠或人类中还没有发现在皮质中保留CD4(+)CD8(+)双阳性(DP)胸腺细胞并阻止它们在阳性选择之前进入髓质的信号。在这里，我们研究了人胸腺细胞在小鼠和人胸腺基质中的胸腺内迁移，发现人胸腺细胞亚群适当地定位于小鼠胸腺基质上的皮质，并且人胸腺细胞与小鼠基质之间依赖MHC的相互作用可以维持DP细胞的激活和运动。我们还表明，CXCR4需要将人的胸腺细胞保留在皮质中，而CCR7则促进成熟的人胸腺细胞向髓质的迁移。因此，两种相反的趋化因子梯度控制胸腺细胞从皮质向髓质的迁移。这些结果表明胸腺细胞-间质相互作用具有显著的种间保守性，并首次证明趋化因子不仅能吸引成熟的胸腺细胞进入髓质，而且在积极选择之前在保留胸腺细胞的皮质中发挥积极的作用。
The ordered migration of thymocytes from the cortex to the medulla is critical for the appropriate selection of the mature T cell repertoire. Most studies of thymocyte migration rely on mouse models, but we know relatively little about how human thymocytes find their appropriate anatomical niches within the thymus. Moreover, the signals that retain CD4(+)CD8(+) double-positive (DP) thymocytes in the cortex and prevent them from entering the medulla prior to positive selection have not been identified in mice or humans. Here, we examined the intrathymic migration of human thymocytes in both mouse and human thymic stroma and found that human thymocyte subsets localized appropriately to the cortex on mouse thymic stroma and that MHC-dependent interactions between human thymocytes and mouse stroma could maintain the activation and motility of DP cells. We also showed that CXCR4 was required to retain human DP thymocytes in the cortex, whereas CCR7 promoted migration of mature human thymocytes to the medulla. Thus, 2 opposing chemokine gradients control the migration of thymocytes from the cortex to the medulla. These fmdings point to significant interspecies conservation in thymocyte-stroma interactions and provide the first evidence that chemokines not only attract mature thymocytes to the medulla, but also play an active role in retaining DP thymocytes in the cortex prior to positive selection.