Impaired Th1 responses in mice deficient in Epstein-Barr virus-induced gene 3 and challenged with physiological doses of Leishmania major.
Protection against Leishmania major is dependent on IL-12 release from L. major-infected dendritic cells (DC) that induce IFN-gamma-producing Th1/Tc1 cells. IL-27, a novel member of the IL-12 family, is a heterodimer composed of p28 and IL-12p40-related Epstein-Barr virus-induced gene 3 (EBI3), and was shown to be produced by DC. In this study, we utilized EBI3-deficient mice to investigate the role of IL-27 in leishmaniasis using physiological low-dose infections that mimic natural transmissions. Lesions in EBI3(-/-) mice were significantly larger between weeks 3 and 10 post infection, reaching up to approximately threefold increased lesion volumes compared to wild types. In parallel, dermal lesions of EBI3(-/-) mice contained greater parasite numbers, reaching a peak load that was 2-log higher than in C57BL/6 mice. However, lesions in EBI3(-/-) and wild-type mice resolved after 12 weeks. At early time points, the antigen-specific cytokine response in EBI3(-/-) lymph nodes showed increased levels of IL-4, IL-10 and IL-13 and decreased IFN-gamma production. IL-27 production was restricted to the DC population, since the majority of EBI3 expression in lymph nodes of infected mice was found in CD11c(+) cells. In conclusion, our data show that DC-derived IL-27 is critical for the timely initiation of efficient anti-parasite Th1 immunity early in infections.
Zahn
Sabine
S
Department of Dermatology, Johannes Gutenberg-University of Mainz, Mainz, Germany.
Wirtz
Stefan
S
Birkenbach
Mark
M
Blumberg
Richard S
RS
Neurath
Markus F
MF
von Stebut
Esther
E
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
C499601:Ebi3 protein, mouse; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D018121:Receptors, Cytokine