Impaired Th1 responses in mice deficient in Epstein‐Barr virus‐induced gene 3 and challenged with physiological doses of Leishmania 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.

Lung CD11c+ cells from mice deficient in Epstein‐Barr virus‐induced gene 3 (EBI‐3) prevent airway hyper‐responsiveness in experimental asthma

“…Moreover, repeated antigen challenge in lung EBI-3 -/-CD11c + cells led to increased release of IFN-c or IL-12 while IFN-a continued to be down-regulated as compared to wildtype lung CD11c + cells. This could be consistent with the findings in the L. major model in which targeted deletion of EBI-3 led to increased production of IFN-c by total cells isolated from lymph nodes [39]. Importantly, we defined here for the first time that the cells overproducing IFN-c in EBI-3-deficient mice are CD11c + and not CD4 + T cells, as they are CD3 -.…”

“…Moreover, this cytokine profile seems to be dependent on the type and amount of antigen presented to the DC. In fact, we found, similarly to data in experimental colitis [29] and in contrast to the L. major model [39], reduced production of two Th2 cytokines in EBI-3-deficient mice, as EBI-3-deficient lung CD4 + T cells produced less IL-4 and IL-5 as compared to wild-type CD4 + T cells in a murine model of asthma after OVA sensitization and challenge. Moreover, repeated antigen challenge in lung EBI-3 -/-CD11c + cells led to increased release of IFN-c or IL-12 while IFN-a continued to be down-regulated as compared to wildtype lung CD11c + cells.…”

“…CD4 + T cells isolated from the lungs of OVA-sensitized and -challenged mice were incubated overnight in the presence of plate-bound anti-CD3 and soluble anti-CD28 antibodies. The supernatants were then analyzed by FACS by using a CBA (mouse Th1/Th2 kit obtained from BD Bioscience Pharmingen, San Diego, CA) in accordance with the manufacturer's instructions and as previously described [38,39]. Following flow cytometric acquisition, the sample results were generated in graphical and tabular formats using the BD CBA Analysis Software (BD PharMingen).…”

Epstein‐Barr virus‐induced gene 3 negatively regulates IL‐17, IL‐22 and RORγt

“…Our current study indicates that EBI3 may play different role in the immunity to L. major and L. monocytogenes. Zahn et al [18] reported that EBI3-deficient mice showed impaired Th1 response and impaired protection to Leishmania major at the early stage when mice were challenged with low doses of L. major. However, at the late stage of infection, enhanced Th1 cytokine IFN-c and reduced Th2 cytokine IL-4 production were observed.…”

“…EBI3-deficient mice exhibit disrupted Th2 responses likely due to altered invariant natural killer T cell function [17]. However, impaired Th1 responses to Leishmania major in EBI3-deficient mice were also reported [18]. More recently, EBI3-deficient mice were reported to display enhanced neutrophil migration and oxidative burst capacity in a murine model of peritonitis, resulting in enhanced bacterial clearance and local control of infection [19].…”