IL-12-independent IFN-gamma production by T cells in experimental Chagas' disease is mediated by IL-18.
IL-12p35-deficient (IL-12p35(-/-)) mice were highly susceptible to Trypanosoma cruzi infection and succumbed during acute infection, demonstrating the crucial importance of endogenous IL-12 in resistance to experimental Chagas' disease. Delayed immune responses were observed in mutant mice, although comparable IFN-gamma and TNF-alpha blood levels as in wild-type mice were detected 2 wk postinfection. In vivo and in vitro analysis demonstrated that T cells, but not NK cells, were recruited to infected organs. Analysis of mice double deficient in the recombinase-activating gene 2 (RAG2) and IL-12p35, as well as studies involving T cell depletion, identified CD4(+) T cells as the cellular source for IL-12-independent IFN-gamma production. IL-18 was induced in IL-12p35(-/-) mice and was responsible for IFN-gamma production, as demonstrated by in vivo IL-18 neutralization studies. In conclusion, evidence is presented for an IL-12-independent IFN-gamma production in experimental Chagas' disease that is T cell and IL-18 dependent.
Müller
U
U
Max Planck Institute for Immunobiology and Department of Pathology, Freiburg, Germany.
Köhler
G
G
Mossmann
H
H
Schaub
G A
GA
Alber
G
G
Di Santo
J P
JP
Brombacher
F
F
Hölscher
C
C
D000208:Acute Disease; D000818:Animals; D014355:Chagas Disease / Q000097:blood / Q000276:immunology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005609:Free Radicals; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics; D020382:Interleukin-18 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009584:Nitrogen / Q000378:metabolism; D018512:Parasitemia / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D004268:DNA-Binding Proteins; D005609:Free Radicals; D020382:Interleukin-18; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C064655:V(D)J recombination activating protein 2; D018664:Interleukin-12; D007371:Interferon-gamma; D009584:Nitrogen