Matsumura Yumiko, Kobayashi Takashi, Ichiyama Kenji, Yoshida Ryoko, Hashimoto Masayuki, Takimoto Tomohito, Tanaka Kentaro, Chinen Takatoshi, Shichita Takashi, Wyss-Coray Tony, Sato Katsuaki, Yoshimura Akihiko
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
J Immunol. 2007 Aug 15;179(4):2170-9. doi: 10.4049/jimmunol.179.4.2170.
Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10(+) Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4(+) T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3(+) Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3(+) T cell-inducing tolerogenic DCs. SOCS3(-/-) DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3(-) effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3(+) Treg cells were selectively expanded by SOCS3(-/-) DCs. Adoptive transfer of SOCS3(-/-) DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3(+) T cell expansion was blocked by anti-TGF-beta Ab, and SOCS3(-/-) DCs produced higher levels of TGF-beta than WT-DCs, suggesting that TGF-beta plays an essential role in the expansion of Foxp3(+) Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.
树突状细胞（DCs）作为抗原呈递细胞（APCs）可诱导免疫和免疫耐受。研究表明，分泌白细胞介素-10（IL-10）的DCs可诱导产生IL-10（+）Tr1型调节性T（Treg）细胞，而通过与成熟DCs共培养，Foxp3阳性Treg细胞可从初始CD4（+）T细胞中扩增出来。然而，DCs对Foxp3（+）Treg细胞扩增的调节机制尚未阐明。在本研究中，我们证明细胞因子信号转导抑制因子（SOCS）-3缺陷型DCs作为诱导Foxp3（+）T细胞的耐受性DCs具有强大的潜能。在体外和体内，SOCS3（-/-）DCs表达的II类主要组织相容性复合体（MHC）、CD40、CD86和IL-12水平均低于野生型（WT）DCs，并显示出信号转导和转录激活因子3（STAT3）的组成性激活。Foxp3（-）效应T细胞主要通过WT-DCs的致敏而扩增，而Foxp3（+）Treg细胞则被SOCS3（-/-）DCs选择性扩增。SOCS3（-/-）DCs的过继转移减轻了实验性自身免疫性脑脊髓炎的严重程度。抗转化生长因子-β（TGF-β）抗体可阻断Foxp3（+）T细胞的扩增，且SOCS3（-/-）DCs产生的TGF-β水平高于WT-DCs，这表明TGF-β在Foxp3（+）Treg细胞的扩增中起重要作用。这些结果表明SOCS3在DCs决定免疫或耐受方面具有重要作用。
