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      Dendritic Cells Promote Treg Expansion but Not Th17 Generation in Response to Talaromyces marneffei Yeast Cells

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          Abstract

          Background

          Dendritic cells (DCs) with both proinflammatory and tolerogenic properties have been implicated in modulation of CD4 + T cell responses in many fungal diseases. However, the role of DC in the context of Talaromyces marneffei ( T. marneffei) infection has not been determined. In this study, we aimed to study the effect of the yeast form of T. marneffei yeasts on DCs, as well as the role of DCs in modulating T helper 17 (Th17) and regulatory T (Treg) cell responses to the pathogen.

          Methods

          Mouse bone marrow-derived DCs were stimulated with T. marneffei yeasts for 24 h. Frequencies of CD80 and CD86 expression on DCs and the levels of IL-6, IL-10 and TGF-β in the culture supernatant of yeast-stimulated DCs were detected by flow cytometry and ELISA, respectively. In co-culture experiments, CD4 + T lymphocytes of mice were isolated from the spleen using magnetic beads and co-cultured with T. marneffei yeasts, with or without DCs for 24 h. The proportions of Th17 and Treg cells in co-culture were detected by flow cytometry. The mRNA levels of RORγt and Foxp3 were detected by RT-PCR. Levels of IL-10 and TGF-β in the co-culture supernatant were detected by ELISA.

          Results

          The expressions of CD80 and CD86 on DCs were increased, as well as IL-6, IL-10 and TGF-β levels in the culture supernatant of T. marneffei-stimulated DCs were higher than those in DCs cultured without T. marneffei. In co-culture experiments, in the presence of DCs, T. marneffei promoted Treg expansion and Foxp3 up-regulation but limited Th17 and downregulated RORγt. Levels of IL-10 and TGF-β were higher in the co-culture containing DCs than without DCs.

          Conclusion

          Our findings demonstrated that the interaction between DCs and T. marneffei could promote Treg expansion but not Th17 generation. These findings provide a mechanism by which DCs may promote immune tolerance in T. marneffei infection.

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          Most cited references39

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          Th17 and regulatory T cell balance in autoimmune and inflammatory diseases.

          This review focuses on the biology of T helper 17 (Th17) and regulatory T (Treg) cells and their role in inflammatory diseases, such as rheumatoid arthritis. Th17 cells represent a pro-inflammatory subset whereas Treg cells have an antagonist effect. Their developmental pathways are reciprocally interconnected and there is an important plasticity between Th17 and Treg cells. These features implicate that the Th17/Treg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases. During these diseases, this balance is disturbed and this promotes the maintenance of inflammation. Targeting the Th17/Treg imbalance can be performed at different levels such as inhibition of pro-inflammatory cytokines and their receptors, of pathogenic cells or their specific signaling pathways. Conversely, direct effects include administration or induction of protective cells, or stimulation of their specific pathways. Several clinical trials are underway and some positive results have been obtained. Copyright © 2014 Elsevier B.V. All rights reserved.
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            Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans.

            Dectin-2 (gene symbol Clec4n) is a C-type lectin expressed by dendritic cells (DCs) and macrophages. However, its functional roles and signaling mechanisms remain to be elucidated. Here, we generated Clec4n(-/-) mice and showed that this molecule is important for host defense against Candida albicans (C. albicans). Clec4n(-/-) DCs had virtually no fungal alpha-mannan-induced cytokine production. Dectin-2 signaling induced cytokines through an FcRgamma chain and Syk-CARD9-NF-kappaB-dependent signaling pathway without involvement of MAP kinases. The yeast form of C. albicans induced interleukin-1beta (IL-1beta) and IL-23 secretion in a Dectin-2-dependent manner. In contrast, cytokine production induced by the hyphal form was only partially dependent on this lectin. Both yeast and hyphae induced Th17 cell differentiation, in which Dectin-2, but not Dectin-1, was mainly involved. Because IL-17A-deficient mice were highly susceptible to systemic candida infection, this study suggests that Dectin-2 is important in host defense against C. albicans by inducing Th17 cell differentiation. Copyright 2010 Elsevier Inc. All rights reserved.
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              Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects.

              Penicillium marneffei infection is an important emerging public health problem, especially among patients infected with human immunodeficiency virus in the areas of endemicity in southeast Asia, India, and China. Within these regions, P. marneffei infection is regarded as an AIDS-defining illness, and the severity of the disease depends on the immunological status of the infected individual. Early diagnosis by serologic and molecular assay-based methods have been developed and are proving to be important in diagnosing infection. The occurrence of natural reservoirs and the molecular epidemiology of P. marneffei have been studied; however, the natural history and mode of transmission of the organism remain unclear. Soil exposure, especially during the rainy season, has been suggested to be a critical risk factor. Using a highly discriminatory molecular technique, multilocus microsatellite typing, to characterize this fungus, several isolates from bamboo rats and humans were shown to share identical multilocus genotypes. These data suggest either that transmission of P. marneffei may occur from rodents to humans or that rodents and humans are coinfected from common environmental sources. These putative natural cycles of P. marneffei infection need further investigation. Studies on the fungal genetics of P. marneffei have been focused on the characterization of genetic determinants that may play important roles in asexual development, mycelial-to-yeast phase transition, and the expression of antigenic determinants. Molecular studies have identified several genes involved in germination, hyphal development, conidiogenesis, and yeast cell polarity. A number of functionally important genes, such as the malate synthase- and catalase-peroxidase protein-encoding genes, have been identified as being upregulated in the yeast phase. Future investigations pertaining to the roles of these genes in host-fungus interactions may provide the key knowledge to understanding the pathogenicity of P. marneffei.
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                Author and article information

                Journal
                Infect Drug Resist
                Infect Drug Resist
                IDR
                idr
                Infection and Drug Resistance
                Dove
                1178-6973
                11 March 2020
                2020
                : 13
                : 805-813
                Affiliations
                [1 ]Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi, People’s Republic of China
                Author notes
                Correspondence: Jianquan Zhang Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi, People’s Republic of China Tel/Fax +86 7715350031 Email jqzhang2002@126.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0003-3656-3895
                Article
                239906
                10.2147/IDR.S239906
                7075240
                32210595
                55cd6241-01e7-4d17-8ef9-540b7513ea02
                © 2020 Tang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 25 November 2019
                : 25 February 2020
                Page count
                Figures: 4, References: 43, Pages: 9
                Categories
                Original Research

                Infectious disease & Microbiology
                dendritic cells,talaromyces marneffei,th17 cells, treg cells

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