Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
Int Immunol. 2010 Dec;22(12):941-52. doi: 10.1093/intimm/dxq448. Epub 2010 Nov 8.
T-cell immune responses are critical for protection of the host and for disease pathogenesis during infection with Plasmodium species. We examined the regulation of CD4(+) T-cell cytokine responses during infection with Plasmodium berghei ANKA (PbA). CD4(+) T cells from PbA-infected mice produced IFN-γ, IL-4 and IL-10 in response to TCR stimulation at levels higher than those from uninfected mice. This altered cytokine response was dependent on parasitemia. To examine the specificity of the response, mice were adoptively transferred with CD4(+) T cells from OT-II TCR transgenic mice and were infected with PbA expressing OVA. Unexpectedly, CD4(+) T cells from the OT-II-transferred wild-type PbA-infected mice showed high levels of IFN-γ production after stimulation with OVA and the cells producing IFN-γ were not OT-II but were host CD4(+) T cells. Further investigation revealed that host CD4(+) T cells produced IFN-γ in response to IL-2 produced by activated OT-II cells. This IFN-γ response was completely inhibited by anti-CD25 mAbs, and this effect was not due to the block of the survival signals provided by IL-2. Furthermore, IFN-γ production by CD4(+) T cells in response to PbA antigens was dependent on IL-2. These findings suggest the importance of IL-2 levels during infection with malaria parasites and indicate that CD4(+) T cells can produce IFN-γ without TCR engagement via a bystander mechanism in response to IL-2 produced by other activated CD4(+) T cells.
T 细胞免疫应答对于宿主的保护和疟原虫感染期间的疾病发病机制至关重要。我们研究了感染疟原虫伯氏疟原虫（PbA）期间 CD4+T 细胞细胞因子反应的调节。与未感染的小鼠相比，PbA 感染小鼠的 CD4+T 细胞在 TCR 刺激下产生 IFN-γ、IL-4 和 IL-10 的水平更高。这种改变的细胞因子反应依赖于寄生虫血症。为了研究反应的特异性，用 OT-II TCR 转基因小鼠的 CD4+T 细胞过继转移小鼠，并感染表达 OVA 的 PbA。出乎意料的是，来自 OT-II 转移的野生型 PbA 感染小鼠的 CD4+T 细胞在用 OVA 刺激后显示出高水平的 IFN-γ产生，产生 IFN-γ 的细胞不是 OT-II，而是宿主 CD4+T 细胞。进一步的研究表明，宿主 CD4+T 细胞在受到激活的 OT-II 细胞产生的 IL-2 的刺激下产生 IFN-γ。这种 IFN-γ 反应完全被抗 CD25 mAb 抑制，并且这种效应不是由于阻断了 IL-2 提供的生存信号所致。此外，CD4+T 细胞对 PbA 抗原的 IFN-γ 产生依赖于 IL-2。这些发现表明在感染疟原虫期间 IL-2 水平的重要性，并表明 CD4+T 细胞可以通过旁分泌机制在没有 TCR 参与的情况下产生 IFN-γ，以响应其他激活的 CD4+T 细胞产生的 IL-2。
