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Activation of invariant NKT cells exacerbates experimental visceral leishmaniasis.
- Source :
-
PLoS pathogens [PLoS Pathog] 2008 Feb 29; Vol. 4 (2), pp. e1000028. Date of Electronic Publication: 2008 Feb 29. - Publication Year :
- 2008
-
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 alpha-galactosylceramide (alpha-GalCer) during L. donovani infection exacerbated, rather than ameliorated, experimental visceral leishmaniasis. The inability of alpha-GalCer to promote anti-parasitic immunity did not result from inefficient antigen presentation caused by infection because alpha-GalCer-loaded bone marrow-derived dendritic cells were also unable to improve disease resolution. The immune-dampening affect of alpha-GalCer correlated with a bias towards increased IL-4 production by iNKT cells following alpha-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 alpha-GalCer-induced IL-4 production during infection had only a minor role in impaired parasite control. Analysis of liver cell composition following alpha-GalCer stimulation during an established L. donovani infection revealed important differences, predominantly a decrease in IFNgamma+ 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.
- Subjects :
- Animals
Antibodies, Blocking pharmacology
Biomarkers
CD8-Positive T-Lymphocytes
Disease Models, Animal
Female
Galactosylceramides therapeutic use
Gene Silencing
Host-Parasite Interactions
Immunologic Factors therapeutic use
Interferon-gamma
Interleukin-4 deficiency
Interleukin-4 immunology
Interleukin-4 metabolism
Leishmania donovani immunology
Leishmaniasis, Visceral drug therapy
Leishmaniasis, Visceral pathology
Liver drug effects
Liver metabolism
Liver parasitology
Lymphocyte Activation
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
RNA, Messenger metabolism
Killer Cells, Natural immunology
Leishmania donovani pathogenicity
Leishmaniasis, Visceral immunology
Lymphocyte Subsets immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 4
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 18463695
- Full Text :
- https://doi.org/10.1371/journal.ppat.1000028