Department of Biochemistry, University of Lausanne, Lausanne, Switzerland.
Eur J Immunol. 2014 May;44(5):1422-32. doi: 10.1002/eji.201344242. Epub 2014 Mar 25.
Leishmania major infection induces self-healing cutaneous lesions in C57BL/6 mice. Both IL-12 and IFN-γ are essential for the control of infection. We infected Jun dimerization protein p21SNFT (Batf3(-/-) ) mice (C57BL/6 background) that lack the major IL-12 producing and cross-presenting CD8α(+) and CD103(+) DC subsets. Batf3(-/-) mice displayed enhanced susceptibility with larger lesions and higher parasite burden. Additionally, cells from draining lymph nodes of infected Batf3(-/-) mice secreted less IFN-γ, but more Th2- and Th17-type cytokines, mirrored by increased serum IgE and Leishmania-specific immunoglobulin 1 (Th2 indicating). Importantly, CD8α(+) DCs isolated from lymph nodes of L. major-infected mice induced significantly more IFN-γ secretion by L. major-stimulated immune T cells than CD103(+) DCs. We next developed CD11c-diptheria toxin receptor: Batf3(-/-) mixed bone marrow chimeras to determine when the DCs are important for the control of infection. Mice depleted of Batf-3-dependent DCs from day 17 or wild-type mice depleted of cross-presenting DCs from 17-19 days after infection maintained significantly larger lesions similar to mice whose Batf-3-dependent DCs were depleted from the onset of infection. Thus, we have identified a crucial role for Batf-3-dependent DCs in protection against L. major.
大耳蝠感染诱导 C57BL/6 小鼠自我修复皮肤损伤。IL-12 和 IFN-γ 对于控制感染都是必不可少的。我们感染了 Jun 二聚化蛋白 p21SNFT（Batf3(-/-)）小鼠（C57BL/6 背景），这些小鼠缺乏主要的产生和交叉呈递 CD8α(+)和 CD103(+) DC 亚群的 IL-12。Batf3(-/-) 小鼠表现出更高的易感性，病变更大，寄生虫负担更高。此外，来自感染 Batf3(-/-) 小鼠引流淋巴结的细胞分泌的 IFN-γ 较少，但 Th2 和 Th17 型细胞因子较多，反映在血清 IgE 和利什曼原虫特异性免疫球蛋白 1（Th2 指示）增加。重要的是，从 L. major 感染的小鼠淋巴结中分离的 CD8α(+) DC 比 CD103(+) DC 诱导更多的 IFN-γ 分泌由 L. major 刺激的免疫 T 细胞。接下来，我们开发了 CD11c-白喉毒素受体：Batf3(-/-)混合骨髓嵌合体，以确定 DC 在控制感染方面的重要性。从第 17 天开始耗尽 Batf-3 依赖性 DC 的小鼠或从感染后 17-19 天开始耗尽交叉呈递 DC 的野生型小鼠，其病变明显大于从感染开始时耗尽 Batf-3 依赖性 DC 的小鼠。因此，我们已经确定了 Batf-3 依赖性 DC 在抵抗 L. major 中的关键作用。
