Abstract
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.
Highlights
Natural killer T (NKT) cells are a unique subset of CD1drestricted T cells that provide a link between innate and adaptive immune responses
Natural killer T (NKT) cells are a unique subset of T cells that can produce large quantities of inflammatory cytokines very rapidly upon stimulation
We attempted to stimulate natural killer T (NKT) cells with aGalCer in mice infected with Leishmania donovani, a protozoan parasite that causes a chronic disease known as visceral leishmaniasis in humans
Summary
Natural killer T (NKT) cells are a unique subset of CD1drestricted T cells that provide a link between innate and adaptive immune responses. The activation of iNKT cells by a-GalCer can enhance resistance in several infectious disease models, including viral, bacterial and parasitic infections (reviewed in [10,11,12]). The ability of iNKT cells to produce IFNc following stimulation with a-GalCer is important for this therapeutic effect and host protection during infection, the robust induction of TNF, IL-4 and IL-13 by iNKT cells occurs There are parallels between physiological and therapeutic NKT cell responses in some disease models. In experimental tumour models, the growth of methylcholanthrene (MCA)-induced sarcoma cell lines is restricted by physiological IFNc produced by endogenous NKT cells [18], while many other experimental cell lines, including the B16-F10 melanoma are only controlled by NKT cells following therapeutic activation with a-GalCer, again in an IFNc-dependent manner [7]. It is possible that following pathogen challenge, NKT cells will be exposed to foreign glycolipids, or self glycolipids, that, in the inflammatory environment, can trigger NKT cell responses that are similar to those induced by a-GalCer [19,20,21,22] (reviewed in [23])
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