Department of Veterinary Microbiology, of Saskatchewan, Saskatoon, Saskatchewan, Canada.
J Immunol. 2010 Nov 1;185(9):5003-10. doi: 10.4049/jimmunol.0903446. Epub 2010 Sep 24.
IL-10-differentiated dendritic cells (DC10) induce allergen tolerance in asthmatic mice, during which their lung Th2 effector T cells (Teffs) are displaced by activated CD4(+)CD25(hi)Foxp3(+) T cells. Intestinal DCs promote oral tolerance by inducing Ag-naive T cells to differentiate into CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), but whether DCs can induce Teffs to differentiate into Tregs remains uncertain. In this study, we addressed this question in OVA-asthmatic mice that were treated with DC10. OVA-presenting DC10 treatment maximally activated lung Tregs in these animals at 3 wk posttreatment, as determined by upregulation of activation markers (ICOS, programmed cell death-1, glucocorticoid-induced TNFR-related protein, LAG3, and CTLA-4) and in functional assays. This in vitro regulatory activity was ≥90% reduced by treatment with anti-IL-10 but not anti-TGF-β Abs. In parallel cultures, OVA- but not house dust mite (HDM)-presenting DC10 induced ≈43% of CFSE-labeled CD25(-/lo)Foxp3(-) Teffs from asthmatic OVA-TCR transgenic mice to differentiate into tolerogenic CD25(hi)Foxp3(+) Tregs. We recapitulated this in vivo using OVA-asthmatic mice that were coinjected with OVA- or HDM-presenting DC10 (i.p.) and CFSE-labeled CD4(+)CD25(-/lo)Foxp3(-) Teffs (i.v.) from the lungs of asthmatic DO11.10 mice. From ≈7 to 21% of the activated (i.e., dividing) DO11.10 Teffs that were recovered from the lungs, lung-draining lymph nodes, or spleens of the OVA-DC10 recipients had differentiated into CD4(+)CD25(hi)Foxp3(+) Tregs, whereas no CFSE-positive Tregs were recovered from the HDM-DC10-treated animals. These data indicate that DC10 treatments induce tolerance at least in part by inducing Teffs to differentiate into CD4(+)CD25(hi)Foxp3(+) Tregs.
白细胞介素-10 分化的树突状细胞（DC10）可诱导哮喘小鼠中的变应原耐受，在此过程中，其肺部 Th2 效应 T 细胞（Teffs）被激活的 CD4(+)CD25(hi)Foxp3(+)T 细胞取代。肠道树突状细胞通过诱导 Ag 幼稚 T 细胞分化为 CD4(+)CD25(+)Foxp3(+)调节性 T 细胞（Tregs）来促进口服耐受，但树突状细胞是否能诱导 Teffs 分化为 Tregs 尚不确定。在本研究中，我们在接受 DC10 治疗的 OVA 哮喘小鼠中研究了这个问题。在治疗后 3 周，OVA 呈递的 DC10 治疗最大程度地激活了这些动物肺部的 Tregs，这可通过上调激活标志物（ICOS、程序性细胞死亡-1、糖皮质激素诱导的 TNFR 相关蛋白、LAG3 和 CTLA-4）和功能测定来确定。这种体外调节活性被抗 IL-10 但不被抗 TGF-βAbs 处理降低了≥90%。在平行培养物中，OVA-而非屋尘螨（HDM）呈递的 DC10 诱导来自哮喘 OVA-TCR 转基因小鼠的约 43%的 CFSE 标记的 CD25(-/lo)Foxp3(-)Teffs 分化为耐受性 CD25(hi)Foxp3(+)Tregs。我们在接受 OVA 哮喘小鼠的体内实验中重现了这一现象，这些小鼠腹腔注射 OVA 或 HDM 呈递的 DC10（i.p.），并静脉注射来自哮喘 DO11.10 小鼠肺部的 CFSE 标记的 CD4(+)CD25(-/lo)Foxp3(-)Teffs（i.v.）。从 OVA-DC10 受者肺部、引流淋巴结或脾脏中回收的约 7%至 21%的激活（即分裂）的 DO11.10 Teffs 已分化为 CD4(+)CD25(hi)Foxp3(+)Tregs，而从 HDM-DC10 处理的动物中未回收 CFSE 阳性 Tregs。这些数据表明，DC10 治疗通过诱导 Teffs 分化为 CD4(+)CD25(hi)Foxp3(+)Tregs 至少部分诱导了耐受。
