Activation of Invariant NKT Cells Exacerbates Experimental Visceral Leishmaniasis

We report that natural killer T (NKT) cells play only a minor physiological role in protection from Leishmania donovani infection in C57BL/6 mice. Furthermore, attempts at therapeutic activation of invariant NKT (iNKT) cells with α-galactosylceramide (α-GalCer) during L. donovani infection exacerbated, rather than ameliorated, experimental visceral leishmaniasis. The inability of α-GalCer to promote anti-parasitic immunity did not result from inefficient antigen presentation caused by infection because α-GalCer–loaded bone marrow–derived dendritic cells were also unable to improve disease resolution. The immune-dampening affect of α-GalCer correlated with a bias towards increased IL-4 production by iNKT cells following α-GalCer stimulation in infected mice compared to naïve controls. However, studies in IL-4–deficient mice, and IL-4 neutralisation in cytokine-sufficient mice revealed that α-GalCer–induced IL-4 production during infection had only a minor role in impaired parasite control. Analysis of liver cell composition following α-GalCer stimulation during an established L. donovani infection revealed important differences, predominantly a decrease in IFNγ+ CD8+ T cells, compared with control-treated mice. Our data clearly illustrate the double-edged sword of NKT cell–based therapy, showing that in some circumstances, such as when sub-clinical or chronic infections exist, iNKT cell activation can have adverse outcomes.

本研究报道，在C57BL/6小鼠中，自然杀伤T（NKT）细胞在抵御杜氏利什曼原虫感染的生理保护作用中仅发挥微弱功能。此外，在杜氏利什曼原虫感染期间采用α-半乳糖神经酰胺（α-GalCer）治疗性激活恒定自然杀伤T（iNKT）细胞的尝试，非但未缓解实验性内脏利什曼病，反而加重了病情。α-GalCer无法促进抗寄生虫免疫，并非由感染引发的抗原呈递效率低下所致，因为负载α-GalCer的骨髓来源树突状细胞同样无法改善疾病转归。与未感染对照组相比，感染小鼠在经α-GalCer刺激后，iNKT细胞偏向于产生更多白细胞介素4（IL-4），这与α-GalCer的免疫抑制效应相关。不过，对IL-4缺陷小鼠的研究以及在细胞因子充足小鼠中进行的IL-4中和实验显示，感染期间α-GalCer诱导产生的IL-4，仅在寄生虫清除受损中发挥微弱作用。对已发生杜氏利什曼原虫感染的小鼠在经α-GalCer刺激后的肝脏细胞组成进行分析，结果显示与对照组小鼠相比存在显著差异，其中最主要的变化是干扰素γ（IFNγ）阳性CD8+ T细胞数量减少。本研究数据清晰阐明了基于NKT细胞的治疗手段的双刃剑效应，表明在某些情境下（如存在亚临床或慢性感染时），iNKT细胞激活可能会产生不良后果。