title: Leishmania-infected MHC class IIhigh dendritic cells polarize CD4+ T cells toward a nonprotective T-bet+ IFN-γ+ IL-10+ phenotype.
abstract: 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 II(high)-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.
authors.affiliation: Parasite Disease Group, Institute for Molecular and Cell Biology, University of Porto, 4150-180 Porto, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Resende
authors.forename: Diana
authors.initials: D
authors.lastname: Moreira
authors.forename: Jorge
authors.initials: J
authors.lastname: Augusto
authors.forename: Joana
authors.initials: J
authors.lastname: Cunha
authors.forename: Bruno
authors.initials: B
authors.lastname: Neves
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Cruz
authors.forename: Jérôme
authors.initials: J
authors.lastname: Estaquier
authors.forename: Anabela
authors.initials: A
authors.lastname: Cordeiro-da-Silva
authors.forename: Ricardo
authors.initials: R
authors.lastname: Silvestre
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000276:immunology*; D002478:Cells, Cultured; D002908:Chronic Disease; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D054884:Host-Pathogen Interactions / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency; D018314:Leishmania infantum / Q000276:immunology / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D020825:T-Box Domain Proteins / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology
chemical_list: D000949:Histocompatibility Antigens Class II; C556062:IL10 protein, mouse; D020825:T-Box Domain Proteins; D016753:Interleukin-10; D007371:Interferon-gamma