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

Date Published: September 19, 2013

Publisher: Public Library of Science

Author(s): Yeonseok Chung, Tomohide Yamazaki, Byung-Seok Kim, Yongliang Zhang, Joseph M. Reynolds, Gustavo J. Martinez, Seon Hee Chang, Hoyong Lim, Mark Birkenbach, Chen Dong, Sarah Gaffen.


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.

Partial Text

The generation of pathogen-specific T cell responses is essential for the clearance of infectious agents. This involves the differentiation of naïve T cells into distinct pathogen-specific helper T cell lineages in a process that largely depends on the cytokine milieu created by innate immune cells upon their activation. Among these innate cytokines, the IL-12 family plays a pivotal role during the differentiation of helper T cells by promoting or inhibiting the lineage program of Th1 or Th17 cells. IL-12 and Th1 responses mediate protective immunity against intracellular pathogens such as Mycobacterium tuberculosis, Francisella tularemia, and Listeria monocytogenes[1], [2]. Conversely, the production of IL-23 and the generation of Th17 responses are thought to mediate host defense against extracellular bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, and Citrobacter rodentum[3], [4], [5], [6], as well as fungi such as Candida albicans and Pneumocystis carnii[7], [8]. The function of Th17 cells following intracellular bacterial infection is less clear.

In this study, we comparatively analyzed the contribution of IL-12p35 and IL-27EBI3 to the host defense against the intracellular pathogen Lm. We demonstrate that, although p35−/− mice failed to control bacterial growth, mice deficient in both p35 and EBI3 had no such defect in controlling bacterial growth. Our study also revealed that IL-17 is involved in the protective immunity in p35−/−EBI3−/− mice. Furthermore, administration of Th17 cells as well as recombinant IL-17 and IL-22 significantly suppressed bacterial growth in p35−/− mice. These findings strongly suggest that Lm utilizes IL-27EBI3 to escape Th17-mediated immune surveillance in IL-12p35-deficient mice. Thus, the present study unveils a previously unappreciated immune escape mechanism of intracellular bacteria through IL-27EBI3, and that Th17 responses play an important role in intracellular bacterial infection, especially in the absence of IL-12 and Th1-mediated immunity.




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