NKT cells are critical for the initiation of an inflammatory bowel response against Toxoplasma gondii.
We demonstrated in this study the critical role of NKT cells in the lethal ileitis induced in C57BL/6 mice after infection with Toxoplasma gondii. This intestinal inflammation is caused by overproduction of IFN-gamma in the lamina propria. The implication of NKT cells was confirmed by the observation that NKT cell-deficient mice (Jalpha281(-/-)) are more resistant than C57BL/6 mice to the development of lethal ileitis. Jalpha281(-/-) mice failed to overexpress IFN-gamma in the intestine early after infection. This detrimental effect of NKT cells is blocked by treatment with alpha-galactosylceramide, which prevents death in C57BL/6, but not in Jalpha281(-/-), mice. This protective effect is characterized by a shift in cytokine production by NKT cells toward a Th2 profile and correlates with an increased number of mesenteric Foxp3 lymphocytes. Using chimeric mice in which only NKT cells are deficient in the IL-10 gene and mice treated with anti-CD25 mAb, we identified regulatory T cells as the source of the IL-10 required for manifestation of the protective effect of alpha-galactosylceramide treatment. Our results highlight the participation of NKT cells in the parasite clearance by shifting the cytokine profile toward a Th1 pattern and simultaneously to immunopathological manifestation when this Th1 immune response remains uncontrolled.
Department of Parasitology, Unit of Early Responses to Intracellular Parasites and Immunopathology, Institut Pasteur-Institut National de la Recherche Agronomique, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Catherine
C
Ronet
Sylvie
S
Darche
Maria
M
Leite de Moraes
Sachiko
S
Miyake
Takashi
T
Yamamura
Jacques A
JA
Louis
Lloyd H
LH
Kasper
Dominique
D
Buzoni-Gatel
D000208:Acute Disease; D000818:Animals; D005260:Female; D005699:Galactosylceramides / Q000627:therapeutic use; D007079:Ileitis / Q000276:immunology / Q000401:mortality / Q000469:parasitology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000401:mortality / Q000469:parasitology / Q000517:prevention & control
D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma