Abstract
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.
Highlights
The generation of pathogen-specific T cell responses is essential for the clearance of infectious agents
To determine if the Listeria monocytogenes (Lm) dominant Th1 responses were due to a preferential induction of IL-12 and IL-27, we examined the induction of IL-12 family genes in dendritic cells and macrophages stimulated with lethally irradiated Lm
P352/2 mice failed to control bacterial growth, mice deficient in both p35 and Epstein Barr Virus-Induced 3 (EBI3) had no such defect in controlling bacterial growth
Summary
The generation of pathogen-specific T cell responses is essential for the clearance of infectious agents. This involves the differentiation of naıve 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. The function of Th17 cells following intracellular bacterial infection is less clear
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