In this investigation we show evidence that absence of IL-17A resulted in reduced number of parasites in liver and spleen during experimental visceral leishmaniasis caused by L. donovani. Our data shows that IL-17A response was mediated by double negative CD4-Cd8-TCRβ- T cells and Th17 cells. Additionally, the absence of IL-17A resulted in elevated levels of IFNγ production by CD4+ T cells, suggesting a regulatory role for IL-17A in the protective immune response against L. donovani. Interestingly absence of IL-17A resulted in reduced accumulation of neutrophils and monocytes into the infected tissues. Together these data identify for the first time IL-17A as an unexpected contributor for VL progression.
The expression of IL-17A during VL was found mainly in CD3+CD4-CD8-TCRβ- followed by CD4+ T cells, the former resemble the phenotype of γδ T cells whereas the latter is the classical Th17 phenotype. It is known that γδ T cells are a prominent source of IL-17A at early stages of Listeria infection (28). γδ T cells produce IL-17A after stimulation with DC derived cytokines such as IL-1β, IL-23 or pathogen ligands (29). Stimulation of CD4 T cells with TGFβ and IL-6 or IL-23 also triggers IL-17A production by these cells (13). How IL-17 production is activated during VL has to be further investigated. However, macrophages produce TGFβ and IL-6 after Leishmania infection and represent a candidate to induce IL-17A response during VL (30). Interestingly, both TGFβ and IL-6 play a detrimental role during VL. Indeed mice deficient in IL-6 showed accelerated clearance of L. donovani with increased IFNγ response (31). Also TGFβ has been largely related to mediating susceptibility during Leishmaniasis, mainly by regulating IFNγ production wi...
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...s are the initial IL-17A producing cells, followed by the differentiation of the Th17 cells during VL. Further investigation is required to dissect the importance of these two IL-17A positive populations during VL and their specific role mediating susceptibility and whether time dependent IL-17A production results in immunity or infection during VL.
Immunity and susceptibility during visceral leishmaniasis have been difficult to fit in the classical Th1/Th2 paradigm(12). Contrary to most intracellular infections the Th2 response has not been clearly related with susceptibility. In this regard, our work clearly demonstrate that a T cell derived cytokine IL-17A is involved in VL progression and highlight the complexity of cytokine regulation during this disease.
The authors would like to thank Dr. Yoichiro Iwakura for providing the IL-17-/- mice.
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