A differential behavior among infected and bystander dendritic cells (DCs) has been explored in different infection models. We have analyzed both populations sorted on contact with visceral Leishmania infantum on a susceptible mice model evaluating the subsequent repercussions on adaptive immune response. Our results demonstrate a clear dichotomy between the immunomodulatory abilities of bystander and infected DCs. The bystander population presents increased levels of IL-12p40 and costimulatory molecules being capable to induce CD4+ T cell activation with immune protective capabilities. In contrast, infected DCs, which express lower costimulatory molecules and higher levels of IL-10, promote the development of Leishmania Ag-specific, nonprotective T-bet+IFN-γ+IL-10+ CD4+ T cells with an effector phenotype. This specific polarization was found to be dependent on IL-12p70. Splenic infected DCs recovered from chronic infected animals are similarly capable to polarize ex vivo syngeneic naive CD4+ T cells toward a T-bet+IFN-γ+IL-10+ phenotype. Further analysis revealed that only MHC class IIhigh–infected DCs were responsible for this polarization. The adoptive transfer of such polarized CD4+ T cells facilitates visceral leishmaniasis in BALB/c mice in a clear contrast with their counterpart generated with bystander DCs that significantly potentiate protection. Further, we demonstrated that CD4+ T cells primed by infected DCs in an IL-10 free system, thus deprived of T-bet+IFN-γ+IL-10+ population, restore the immune response and reduce parasite load, supporting a deleterious role of IFN-γ+IL-10+ T cells in the maintenance of infection. Overall, our results highlight novel subversion mechanisms by which nonprotective T-bet+IFN-γ+IL-10+ T cells are associated with chronicity and prolonged parasite persistence.
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