Summary The importance of T helper type 1(Th1) immunity in host resistance to the intracellular bacterium Francisella tularensis is well established. However, the relative roles of Interleukin (IL)-12/Th1 and IL-23/T helper type 17(Th17) responses in immunity to F.tularensis have not been studied. The IL-23/Th17 pathway is critical for protective immunity against extracellular bacterial infections. In contrast, the IL-23/Th17 pathway is dispensable for protection against intracellular pathogens such as Mycobacteria. Our data show that the IL-23/Th17 pathway regulates the IL-12/Th1 pathway and is required for protective immunity against F.tularensis Live Vaccine Strain (LVS). We show that IL-17, but not IL-17F or IL-22 induces IL-12 production in dendritic cells and mediates Th1 responses. Furthermore, we show that IL-17 also induces IL-12 and IFNγ production in macrophages and mediates bacterial killing. Together, these findings illustrate a novel biological function for IL-17 in regulating IL-12/Th1 immunity and host responses to an intracellular pathogen.

IL-23 is required for the IL-17 response to infection with Mycobacterium tuberculosis (Mtb), but is not required for the early control of bacterial growth. However, mice deficient for the p19 component of IL-23 (Il23a−/−) exhibit increased bacterial growth late in infection that is temporally associated with smaller B cell follicles in the lungs. Cxcl13 is required for B cell follicle formation and immunity during tuberculosis. The absence of IL-23 results in decreased expression of Cxcl13 within Mtb-induced lymphocyte follicles in the lungs and this deficiency was associated with increased cuffing of T cells around the vessels in the lungs of these mice. Il23a−/− mice also poorly expressed IL-17A and IL-22 mRNA. These cytokines were able to induce Cxcl13 in mouse primary lung fibroblasts suggesting that these cytokines are likely involved in B cell follicle formation. Indeed, IL-17RA-deficient mice (Il17ra−/−) generated smaller B cell follicles early in the response, whereas IL-22-deficient (Il22−/−) mice had smaller B cell follicles at an intermediate time after infection; however only Il23a−/− mice had a sustained deficiency in B cell follicle formation and reduced immunity. We propose that in the absence of IL-23, expression of long-term immunity to tuberculosis is compromised due to reduced expression of Cxcl13 in B cell follicles and reduced ability of T cells to migrate from the vessels and into the lesion. Further while IL-17 and IL-22 can both contribute to Cxcl13 production and B cell follicle formation it is IL-23 that is critical in this regard.

Purpose of the review-Compelling evidence suggests that the Th17 lineage and other IL-17 producing cells play critical roles in host defense against pathogens at mucosal sites. However, IL-17 can also contribute to inflammatory responses at mucosal sites. In this review, we will discuss the recent progress in our understanding of the role of Th17 and other IL-17-producing cells in defining the fine balance between immunity and inflammation at different mucosal sites.Recent Findings-Recent findings have highlighted that Th17 cytokines are important for the induction of innate and adaptive host responses and contribute to host defense against pathogens at mucosal sites. More recent developments have probed how the Th17 responses are generated in vivo in response to infections and their requirement in maintaining barrier function at mucosal sites. Most importantly, it is becoming apparent that there is a fine balance between protective and pathological manifestation of Th17 responses at mucosal sites that defines immunity or inflammation.Summary-In this review we have summarized the recent advances in our understanding of Th17 cytokines and how they contribute to immunity versus inflammation at mucosal sites.