Ito Hiroaki, Esashi Eiji, Akiyama Taishin, Inoue Jun-ichiro, Miyajima Atsushi
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
Int Immunol. 2006 Aug;18(8):1253-63. doi: 10.1093/intimm/dxl058. Epub 2006 Jun 13.
Thymic dendritic cells (DCs) are suggested to be involved in T cell selection; however, their exact origin and function remain to be established. Although DCs in the adult thymus are mostly CD8alpha(+)CD11b(-), we found that CD8alpha(-)CD11b(+) DCs were abundantly present in the fetal thymus and they possessed antigen-presenting activity. Interestingly, these CD11b(+) DCs were significantly decreased in mice deficient for TNFR-associated factor 6 (TRAF6), a key signaling molecule downstream of IL-1 and tumor necrosis factor-alpha that have been known to induce DCs from intra-thymic precursor cells. CD11b(+) DCs were induced from CD4(-)CD8(-) thymocytes by fetal thymic epithelial cells (TECs). Analysis of cytokine expression in TECs revealed that none of the cytokines previously shown to induce DCs were expressed. Instead, we found strong expression of IL-18 that transmits signals through TRAF6. IL-18 induced CD11b(+) DCs from CD4(-)CD8(-) thymocytes in vitro, which exhibited strong antigen-presenting activity and formed conjugates with CD4(+)CD8(+) T cells efficiently. Taken together, these results strongly suggest that CD11b(+) DCs are differentiated from CD4(-)CD8(-) thymocytes by IL-18 produced from TECs and that they are involved in T cell selection in the fetal thymus.
胸腺树突状细胞（DCs）被认为参与T细胞的选择；然而，它们的确切起源和功能仍有待确定。尽管成年胸腺中的DCs大多为CD8α(+)CD11b(-)，但我们发现CD8α(-)CD11b(+) DCs在胎儿胸腺中大量存在，并且它们具有抗原呈递活性。有趣的是，在缺乏肿瘤坏死因子受体相关因子6（TRAF6）的小鼠中，这些CD11b(+) DCs显著减少，TRAF6是白细胞介素-1和肿瘤坏死因子-α下游的关键信号分子，已知可从胸腺内前体细胞诱导DCs。胎儿胸腺上皮细胞（TECs）可从CD4(-)CD8(-)胸腺细胞诱导出CD11b(+) DCs。对TECs中细胞因子表达的分析表明，先前显示可诱导DCs的细胞因子均未表达。相反，我们发现白细胞介素-18有强烈表达，它通过TRAF6传递信号。白细胞介素-18在体外可从CD4(-)CD8(-)胸腺细胞诱导出CD11b(+) DCs，这些DCs表现出强大的抗原呈递活性，并能有效地与CD4(+)CD8(+) T细胞形成结合物。综上所述，这些结果强烈表明，CD11b(+) DCs由TECs产生的白细胞介素-18从CD4(-)CD8(-)胸腺细胞分化而来，并且它们参与胎儿胸腺中的T细胞选择。
