During acute Trypanosoma cruzi infection highly susceptible mice deficient in natural killer cells are protected by a single alpha-galactosylceramide treatment.
The protective immune response against Trypanosoma cruzi is improved by treatment with the natural killer (NK) T-cell glycolipid antigen alpha-galactosylceramide (alpha-GalCer). A single alpha-GalCer treatment of mice before T. cruzi infection decreases parasitaemia and prolongs survival. This protection is dependent on CD1d-restricted NKT cells and interferon-gamma (IFN-gamma) suggesting that alpha-GalCer-activated NKT cells produce IFN-gamma, which stimulates the cells of the innate and adaptive immune responses to provide protection. To learn which cells provide protection we investigate here alpha-GalCer treatment of mice deficient in different immune cells. Surprisingly, although NK cells provide protection against T. cruzi, and are a major source of IFN-gamma following alpha-GalCer treatment, NK cells are not required for the alpha-GalCer-induced protection. The alpha-GalCer treatment of NK-cell-depleted mice controlled parasitaemia and prevented death. In contrast, phagocytes, helper T cells and cytotoxic T cells are required. Furthermore, alpha-GalCer treatment of MHC II(-/-) or CD8alpha(-/-) mice exacerbated the infection, demonstrating that alpha-GalCer treatment induces some responses that favour the parasite. In summary alpha-GalCer protection against T. cruzi required multiple cellular responses, but not the response of NK cells. These results provide useful information because alpha-GalCer is being developed as therapy for infections, autoimmune diseases, allergy and cancers.
Duthie
Malcolm S
MS
Infectious Disease Research Institute, Seattle, WA 98104, USA.
Kahn
Stuart J
SJ
D000208:Acute Disease; D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005699:Galactosylceramides / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000276:immunology / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects
D016827:CD8 Antigens; C431698:CD8alpha antigen; D005699:Galactosylceramides; D014344:Trypanocidal Agents; C493154:alpha-galactosylceramide