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 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.
Stanley
Amanda C
AC
Immunology and Infection Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia.
Zhou
Yonghong
Y
Amante
Fiona H
FH
Randall
Louise M
LM
Haque
Ashraful
A
Pellicci
Daniel G
DG
Hill
Geoff R
GR
Smyth
Mark J
MJ
Godfrey
Dale I
DI
Engwerda
Christian R
CR
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000627:therapeutic use; D020868:Gene Silencing; D006790:Host-Parasite Interactions; D007155:Immunologic Factors / Q000627:therapeutic use; D007371:Interferon-gamma; D015847:Interleukin-4 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism
D019138:Antibodies, Blocking; D015415:Biomarkers; D005699:Galactosylceramides; D007155:Immunologic Factors; D012333:RNA, Messenger; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma