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      Tolerogenic Plasmacytoid Dendritic Cells Control Paracoccidioides brasiliensis Infection by Inducting Regulatory T Cells in an IDO-Dependent Manner

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          Abstract

          Plasmacytoid dendritic cells (pDCs), considered critical for immunity against viruses, were recently associated with defense mechanisms against fungal infections. However, the immunomodulatory function of pDCs in pulmonary paracoccidiodomycosis (PCM), an endemic fungal infection of Latin America, has been poorly defined. Here, we investigated the role of pDCs in the pathogenesis of PCM caused by the infection of 129Sv mice with 1 x 10 6 P. brasiliensis-yeasts. In vitro experiments showed that P. brasiliensis infection induces the maturation of pDCs and elevated synthesis of TNF-α and IFN-β. The in vivo infection caused a significant influx of pDCs to the lungs and increased levels of pulmonary type I IFN. Depletion of pDCs by a specific monoclonal antibody resulted in a less severe infection, reduced tissue pathology and increased survival time of infected mice. An increased influx of macrophages and neutrophils and elevated presence of CD4 + and CD8 + T lymphocytes expressing IFN-γ and IL-17 in the lungs of pDC-depleted mice were also observed. These findings were concomitant with decreased frequency of Treg cells and reduced levels of immunoregulatory cytokines such as IL-10, TGF-β, IL-27 and IL-35. Importantly, P. brasilienis infection increased the numbers of pulmonary pDCs expressing indoleamine 2,3-dioxygenase-1 (IDO), an enzyme with immunoregulatory properties, that were reduced following pDC depletion. In agreement, an increased immunogenic activity of infected pDCs was observed when IDO-deficient or IDO-inhibited pDCs were employed in co-cultures with lymphocytes Altogether, our results suggest that in pulmonary PCM pDCs exert a tolerogenic function by an IDO-mediated mechanism that increases Treg activity.

          Author Summary

          The fungus Paracoccidioides brasiliensis causes paracoccidioidomycosis (PCM), the most relevant deep mycosis in Latin America. The plasmacytoid dendritic cells (pDCs) are important immune cells involved in protection against viral infections, but their role in fungal infections remains unclear. Here, we investigated the role of pDCs in the pathogenesis of pulmonary PCM using a monoclonal antibody to deplete this DC subset. pDCs depletion leads to a less severe PCM associated with increased T cell response mainly mediated by Th1 and Th17 cells. The lung homogenates of depleted mice showed diminished levels of type I IFN and anti-inflammatory cytokines. In addition, a reduced number of regulatory T cells (Treg) paralleled a diminished number pDCs expressing IDO, a potent immunoregulatory enzyme. In agreement, pDCs of IDO -/- mice or IDO-inhibited pDCs stimulated by P. brasiliensis yeasts expanded elevated numbers of T cells concomitant with a reduced expansion of Treg cells. Taken together, our results demonstrate a tolerogenic activity of pDCs that enhances the severity of a pulmonary mycosis mediated by the concerted action of IDO and Treg cells. These results reveal a new function for pDCs in primary fungal infections and open new perspectives for immunotherapeutic procedures of PCM involving the control of IDO and Treg activity.

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          Most cited references 66

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          Dendritic cells and the control of immunity.

          B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.
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            Plasmacytoid dendritic cells in immunity.

            Human and mouse plasmacytoid dendritic cells have been shown to correspond to a specialized cell population that produces large amounts of type I interferons in response to viruses, the so-called natural interferon-producing cells. As a result, intensive investigation is now focused on the potential functions of plasmacytoid dendritic cells in both innate and adaptive immunity. Here we review recent progress on the characterization of plasmacytoid dendritic cell origin, development, migration and function in immunity and tolerance, as well as their effect on human diseases.
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              Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism

              We have recently shown that expression of the enzyme indoleamine 2,3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell–derived signals IFN-γ and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.
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                Author and article information

                Affiliations
                Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
                University of Pittsburgh, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: EFdA ACN VLGC FVL.

                • Formal analysis: EFdA DHM NAdLG FVL.

                • Funding acquisition: VLGC FVL.

                • Investigation: EFdA DHM NAdLG FVL.

                • Methodology: EFdA VLGC FVL.

                • Project administration: ACN VLGC FVL.

                • Resources: VLGC FVL.

                • Supervision: FVL.

                • Validation: EFdA DHM NAdLG FVL.

                • Visualization: EFdA DHM NAdLG VLGC FVL.

                • Writing – original draft: EFdA VLGC FVL.

                • Writing – review & editing: EFdA ACN VLGC FVL.

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                19 December 2016
                December 2016
                : 12
                : 12
                27992577 5215616 10.1371/journal.ppat.1006115 PPATHOGENS-D-16-01483
                © 2016 Araújo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Figures: 10, Tables: 0, Pages: 29
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                Funding
                This work was supported by a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP- Grant FVL 2014-04783-2; FVL 2014/22630-9; DHM and FVL 2015/12328-6; VLGC and EFdA fellowship to EFdA 2014/18668-0) and Conselho Nacional de Pesquisas (CNPq). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                2017-01-04
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology

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