Epstein Barr Virus-Induced 3 (EBI3) Together with IL-12 Negatively Regulates T Helper 17-Mediated Immunity to Listeria monocytogenes Infection

Although the protective functions by T helper 17 (Th17) cytokines against extracellular bacterial and fungal infection have been well documented, their importance against intracellular bacterial infection remains unclear. Here, we investigated the contribution of Th17 responses to host defense against intracellular bacteria Listeria monocytogenes and found that Th17 cell generation was suppressed in this model. Unexpectedly, mice lacking both p35 and EBI3 cleared L. monocytogenes as efficiently as wild-type mice, whereas p35-deficient mice failed to do so. Furthermore, both innate cells and pathogen-specific T cells from double-deficient mice produced significantly higher IL-17 and IL-22 compared to wild-type mice. The bacterial burden in the liver of double-deficient mice treated with anti-IL-17 was significantly increased compared to those receiving a control Ab. Transfer of Th17 cells specific for listeriolysin O as well as administration of IL-17 and IL-22 significantly suppressed bacterial growth in p35-deficient mice, indicating the critical contribution of Th17 responses to host defense against the intracellular pathogen in the absence of IL-12 and proper Th1 responses. Our findings unveil a novel immune evasion mechanism whereby the intracellular bacteria exploit IL-27EBI3 to suppress Th17-mediated protective immunity.
Author Summary There is a considerable gap in our understanding of how pathogenic intracellular bacteria escape innate and adaptive host immunity. Production of IL-12, and subsequently IFNγ, upon infection triggers host immunity that prevents early dissemination of pathogenic intracellular pathogens. This is evident in observing the increased susceptibility of patients with deficiencies in IL-12, IFNγ, or their receptors to pathogenic intracellular bacteria such as Mycobacterium tuberculosis and Listeria monocytogenes (Lm). Paradoxically, the regulation of host defense by other members of the IL-12 family is poorly understood. Through the use of an animal model of Lm infection, we show that mice lacking IL-27EBI3 were resistant to Lm infection, even in the absence of IL-12. Neutralization and adoptive transfer studies showed that this protection was mediated through IL-17, IL-22 and Th17 responses. Thus our results identify IL-27EBI3 as a critical mechanism for immune escape by Lm in the absence of IL-12-mediated protective immunity. Furthermore, our work suggests that targeting IL-27EBI3 may represent a novel strategy for the treatment of bacterial infection in individuals lacking proper IL-12 responses.