Impact of activated invariant natural killer T cells on the expansion of regulatory T cell precursors in murine thymocytes in vitro
Impact of activated invariant natural killer T cells on the expansion of regulatory T cell precursors in murine thymocytes in vitro
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DOI：
10.1016/j.imlet.2018.11.013
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发表时间：
2019-02-01
影响因子：
4.4
通讯作者：
Tanabe, Kazunari
中科院分区：
文献类型：
--
作者：
Katsumata, Haruki;Ikemiyagi, Masako;Tanabe, Kazunari
诱导耐受是临床移植的一个目标，目的是在不终生使用免疫抑制药物的情况下防止移植物排斥反应。在一系列的小鼠研究中，我们先前报道，通过CD40信号阻断的不变自然杀伤T细胞(INKT)的配体处理建立混合嵌合体，可以在没有免疫抑制剂的情况下防止同种异体移植排斥反应，这种方法在胸腺切除受体小鼠中失败。在这项研究中，我们证明了小鼠胸腺细胞培养中的iNKT细胞对于扩增CD4(+)CD25Foxp3(+)调节性T细胞(Treg)以及含有前体Tregs(PreTregs)的CD4+CD25Foxp3-细胞是必不可少的。小鼠胸腺细胞在iNKT细胞的代表性配体α-GalCer作用下培养后，无论抗CD40 L单抗处理与否，CD_4+CD_(25+)Foxp_3-preTregs/CD_4(+)CD_8T细胞的比例均显著高于CD_4CD_(25+)Foxp_3+Treg细胞。α-GalCer对CD25 Foxp3(-)细胞的增殖有明显的促进作用，但对Treg细胞的增殖无明显影响，Treg细胞的稳定性不受α-GalCer的影响。细胞因子中和不能抑制胸腺细胞来源的Tregs的扩增。然而，在体外，胸腺来源的CD4(+)CD25Foxp3-细胞在IL-2刺激后表达Foxp3，并呈剂量依赖关系。这些结果共同表明，经α-GalCer处理的胸腺来源的Treg细胞在体外的扩增是由CD4(+)CD25 Foxp3(-)preTregs的增殖引起的，而不是现有的Treg细胞。
Tolerance induction is a goal of clinical transplantation to prevent graft rejection without the lifelong use of immunosuppressive drugs. In a series of mouse studies, we previously reported that the establishment of mixed chimerism by treatment with a ligand for invariant natural killer T (iNKT) cells with CD40 signal blockade makes it possible to prevent allograft rejection without immunosuppressants, and this approach fails in thymectomized recipient mice. In this study, we showed that iNKT cells in murine thymocyte cultures are indispensable for the expansion of CD4(+) CD25 Foxp3(+) regulatory T (Treg) cells as well as CD4+CD25 Foxp3- cells, which contained precursor Tregs (preTregs). After the culture of BALB/c mouse-derived thymocytes in the presence of agalactosylceramide (alpha-GalCer), a representative ligand for iNKT cells, the ratio of CD4+CD25+Foxp3- preTregs to total CD4(+)CD8 T cells was much higher than that of CD4 CD25+Foxp3+ Treg cells, regardless of antiCD40 L mAb treatment. The proliferation of CD4(+)CD25 Foxp3(-) cells, but not Treg cells, was significantly augmented, and the stability of Treg cells was not affected by alpha-GalCer. The expansion of thymocyte-derived Tregs was not inhibited by cytokine neutralization. However, in vitro thymus-derived CD4(+)CD25 Foxp3- cells expressed Foxp3 after IL-2 stimulation in a dose-dependent manner. These results collectively suggest that in vitro thymus-derived Treg cell expansion by alpha-GalCer treatment was caused by the proliferation of CD4(+)CD25 Foxp3(-) preTregs but not existing Treg cells.