Impaired Th1 responses in mice deficient in Epstein-Barr virus-induced gene 3 and challenged with physiological doses ofLeishmania major

Abstract

Protection against Leishmania major is dependent on IL‐12 release from L. major‐infected dendritic cells (DC) that induce IFN‐γ‐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‐γ 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.