Epstein-Barr virus-induced gene 3 is a negative regulator of IL-17 and protective immunity against Listeria monocytogenes

The product of the Epstein-Barr virus-induced gene 3 (EBI3) associates with p28, an IL-12p35-related protein, to form IL-27. EBI3 also associates with IL-12p35 to form a distinct heterodimer. The function of EBI3 in innate as well as adaptive immunity to intracellular bacteria has not been established. Here we demonstrate that EBI3 deficient mice exhibit a reduced bacterial load following an acute challenge with Listeria monocytogenes or a re-challenge of animals previously immunized with L. monocytogenes, suggesting EBI3 plays a negative role in both innate and adaptive immunity. The enhanced protective immunity in EBI3-deficient mice is not due to modulation of the Th1 immune response since the production of IFNγ and TNFα was not significantly altered. Importantly, spleen cells from EBI3-deficient mice immunized with L. monocytogenes produced significantly higher levels of IL-17 than wild type cells. Furthermore splenocytes as well as Th17 cells from EBI3-deficient mice secreted increased levels of IL-17. Elevated numbers of IL-17-producing cells were observed when EBI3 deficient CD4+ T cells were cultured under conditions to induce Th17 cell differentiation. Taken together, these data provide direct evidence that EBI3 is an important negative regulator of protective immunity against L. monocytogenes as well as IL-17 expression.