Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells
Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells
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DOI：
10.4049/jimmunol.179.4.2170
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
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作者：
Matsumura, Yumiko;Kobayashi, Takashi;Yoshimura, Akihiko
树突状细胞(DC)作为APC诱导免疫和免疫耐受。已有研究表明，分泌IL-10的DC可诱导IL-10(+)三型调节性T(Treg)细胞，而Foxp3阳性的Treg细胞是通过与成熟的MS共同培养从幼稚的CD4(+)T细胞扩增而来的，但DC扩增Foxp3(+)Treg细胞的调控机制尚不清楚。在这项研究中，我们证明了细胞因子信号转导(SOCS)-3缺陷的DC具有作为Foxp3(+)T细胞诱导耐受的强大潜能，SOCS3(-/-)DC在体外和体内都比野生型(WT)-DC表达更低的11类MHC、CD40、CD86和IL-12，并显示出STAT3的结构性激活。WT-DC可显著扩增Foxp3(-)效应T细胞，而SOCS3(-/-)DC可选择性扩增Foxp3(+)Treg细胞。过继转移SOCS3(-/-)DC可降低实验性自身免疫性脑脊髓炎的严重程度。Foxp3(+)T细胞的增殖可被抗转化生长因子-β抗体阻断，SOCS3(-/-)树突状细胞产生的转化生长因子-β水平高于WT-DC，提示转化生长因子-β在Foxp3(+)Treg细胞的扩增中起重要作用。这些结果表明SOCS3在决定MS的免疫或耐受方面起着重要作用。
Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10(+) TrI-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4(+) T cells by coculturing with mature Ms. 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 Ms. SOCS3(-/-) DCs expressed lower levels of class 11 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 Ms.