Studies in CD1d-deficient BALB/c mice have also suggested that NKT cells are important for the efficient control of growth . antibody. The percentage of gated cells is usually shown in the top left-hand corner. One representative animal of four examined is usually shown.(5.38 MB TIF) ppat.1000028.s003.tif (5.1M) GUID:?9CDEC3C3-CBF7-4B48-ACB6-41C157E73DC0 Figure S4: Liver Cell Composition Following -GalCer Treatment. C57BL/6 mice were infected with and treated with either vehicle control (open bars) or 2 g -GalCer (closed bars) i.p. on day 14 p.i.. Liver cell numbers were determined by FACS in na?ve mice (hatched bars), at day 14 p.i. in untreated mice Fluvastatin sodium (grey bars), and 1 wk later in treated groups, as Rabbit Polyclonal to TUBGCP6 indicated (contamination in C57BL/6 mice. Furthermore, attempts at therapeutic activation of invariant NKT (iNKT) cells with -galactosylceramide (-GalCer) during contamination exacerbated, rather than ameliorated, experimental visceral leishmaniasis. The inability of -GalCer to promote anti-parasitic immunity did not result from inefficient antigen presentation caused by contamination because -GalCerCloaded bone marrowCderived dendritic cells were also unable to improve disease resolution. The immune-dampening affect of -GalCer correlated with a bias towards increased IL-4 production by iNKT cells following -GalCer stimulation in infected mice compared to na?ve controls. However, studies in IL-4Cdeficient mice, and IL-4 neutralisation in cytokine-sufficient mice revealed that -GalCerCinduced IL-4 production during infection had only a minor role in impaired parasite control. Analysis of liver cell composition following -GalCer stimulation during an established infection revealed important differences, predominantly a decrease in IFN+ CD8+ T cells, compared with control-treated mice. Our data clearly illustrate the double-edged sword of NKT cellCbased therapy, showing that in some circumstances, such as when sub-clinical or chronic infections exist, iNKT cell activation can have adverse outcomes. Fluvastatin sodium Author Summary Natural killer T (NKT) cells are a unique subset of T cells that can produce large quantities of inflammatory cytokines very rapidly upon stimulation. They are known to be strongly stimulated by a molecule called -galactosylceramide (-GalCer) that is derived from a marine sponge, and in this way -GalCer is usually hoped to provide effective immunotherapy for a wide range of diseases. We attempted to stimulate NKT Fluvastatin sodium cells with -GalCer in mice infected with characteristically causes an acute resolving contamination in the liver where NKT cells are abundant. Therefore, we hypothesised that by stimulating these cells with -GalCer we would improve the rate of hepatic disease resolution. However, while -GalCer administered prior to contamination had no effect on hepatic parasite burden, -GalCer administered during an established contamination exacerbated hepatic disease, associated with a decrease in IFN-producing CD8+ T cells. These results are important as they demonstrate that therapies aimed at modulating NKT cell function are not always beneficial, and adverse consequences may occur in certain circumstances, such as in the presence of persistent and/or sub-clinical infections. Introduction Natural killer T (NKT) cells are a unique subset of CD1d-restricted T cells that provide a link between innate and adaptive immune responses. In mice, invariant NKT (iNKT) cells express a semi-invariant TCR, consisting of a V14J18 TCR -chain and a TCR Fluvastatin sodium -chain biased towards V8.2, V2, and V7 expression (reviewed in ). Type II NKT cells are another cell subset in mice with more diverse TCR expression C. Upon stimulation, iNKT cells rapidly produce large quantities of pro- and anti-inflammatory cytokines, resulting in activation of other immune cells such as NK cells and conventional T cells C (also reviewed in ). NKT cells recognise and respond to glycolipid antigens presented on CD1d molecules. The most well-defined antigen for iNKT cells is usually -galactosylceramide (-GalCer), a marine sponge-derived glycolipid that specifically targets iNKT cells and no other lymphocyte populations directly . The activation of iNKT cells by -GalCer can enhance resistance in several infectious disease models, including viral, bacterial and parasitic infections (reviewed in C). Among parasitic infections studied, -GalCer has been shown to enhance resistance to malaria , trypanosomiasis  and toxoplasmosis . The ability of iNKT cells to produce IFN following stimulation with -GalCer is usually important for this therapeutic effect and host protection during infection, although the robust induction of TNF, IL-4 and IL-13 by iNKT cells also occurs (reviewed in ,,. However, the connection between therapeutically induced NKT cell responses and physiological NKT cell responses is not always clear. Nevertheless, there are parallels between physiological and therapeutic NKT cell responses in some disease models. For example, in experimental tumour models, the growth of methylcholanthrene (MCA)-induced sarcoma cell lines is restricted by physiological IFN produced by.
Studies in CD1d-deficient BALB/c mice have also suggested that NKT cells are important for the efficient control of growth