Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, Quebec, H3G 1A4 Canada.
J Immunol. 2011 Apr 15;186(8):4862-71. doi: 10.4049/jimmunol.1003777. Epub 2011 Mar 9.
To investigate the role of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in blood-stage malaria, we compared Plasmodium chabaudi AS infection in wild-type (WT) C57BL/6 and transgenic mice overexpressing the transcription factor Foxp3 (Foxp3Tg) and observed that Foxp3Tg mice experienced lethal infection and deficient malaria-specific immune responses. Adoptive transfer of total CD4(+) T cells from Foxp3Tg mice or CD4(+)CD25(+) T cells from WT mice to naive WT recipients confirmed that high numbers of Treg cells compromised immune control of malaria. Transfer of GFP(+)CD4(+)CD25(+) T cells to naive WT recipients together with immunohistochemical staining of spleens from infected WT mice demonstrated that Foxp3(+) Treg cells localized in the T cell area of the spleen. Determination of CD4(+)Foxp3(+) Treg cell responses in the spleen of infected WT mice revealed a significant but transient increase in CD4(+)Foxp3(+) Treg cells early in infection. This was followed by a significant and sustained decrease due to reduced proliferation and apoptosis of CD4(+)Foxp3(+) Treg cells. Importantly, the kinetics of IL-2 secretion by effector CD4(+)Foxp3(-) T cells coincided with changes in CD4(+)Foxp3(+) cells and the differentiation of CD4(+)T-bet(+)IFN-γ(+) cells required for immune control of infection. Administration of the IL-2/anti-IL-2 mAb (clone JES6-1) complex to infected WT mice increased the severity of P. chabaudi AS infection and promoted expansion of Foxp3(+) Treg cells. Collectively, these data demonstrate that the ability to control and eliminate P. chabaudi AS infection is due to a tight balance between natural Treg cells and effector CD4(+) Th1 cells, a balance regulated in part by IL-2.
为了研究 CD4(+)CD25(+)Foxp3(+)调节性 T（Treg）细胞在血期疟原虫感染中的作用，我们比较了野生型（WT）C57BL/6 和过表达转录因子 Foxp3（Foxp3Tg）的转基因小鼠中疟原虫 Chabaudi AS 的感染情况，并观察到 Foxp3Tg 小鼠发生致命性感染和缺乏疟疾特异性免疫应答。从 Foxp3Tg 小鼠中过继转移总 CD4(+)T 细胞或从 WT 小鼠中过继转移 CD4(+)CD25(+)T 细胞到 WT 受体，证实大量 Treg 细胞会损害疟疾的免疫控制。将 GFP(+)CD4(+)CD25(+)T 细胞转移到 WT 受体，并对感染 WT 小鼠的脾脏进行免疫组织化学染色，证明 Foxp3(+)Treg 细胞定位于脾脏的 T 细胞区。在感染 WT 小鼠的脾脏中检测 CD4(+)Foxp3(+)Treg 细胞的反应，发现感染早期 CD4(+)Foxp3(+)Treg 细胞数量显著增加，但持续时间短暂。随后由于 CD4(+)Foxp3(+)Treg 细胞的增殖和凋亡减少，数量显著减少。重要的是，效应性 CD4(+)Foxp3(-)T 细胞分泌 IL-2 的动力学与 CD4(+)Foxp3(+)细胞的变化以及感染免疫控制所需的 CD4(+)T-bet(+)IFN-γ(+)细胞的分化相吻合。向感染 WT 小鼠给予 IL-2/抗 IL-2 mAb（克隆 JES6-1）复合物会增加 P. chabaudi AS 感染的严重程度，并促进 Foxp3(+)Treg 细胞的扩增。总的来说，这些数据表明控制和消除 P. chabaudi AS 感染的能力是由于天然 Treg 细胞和效应性 CD4(+)Th1 细胞之间的紧密平衡，这种平衡部分受 IL-2 调节。
