Depletion of regulatory T cells in ongoing paracoccidioidomycosis rescues protective Th1/Th17 immunity and prevents fatal disease outcome

Galdino, Nayane A. L.; Loures, Flávio Vieira; Araújo, Eliseu Frank de; Costa, Tânia Alves da; Preite, Nycolas Willian; Calich, Vera Lúcia Garcia

doi:10.1038/s41598-018-35037-8

Cited by 28 publications

(27 citation statements)

References 63 publications

(83 reference statements)

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“…Thus, it is unexpected that mucosal Trm producing IL-17 in IN vaccinated mice were non-protective. It is possible that regulatory Trm cells, which are typically not associated with host resistance to fungal infection, dampen the protective effects of Th17 cells (de Araujo et al, 2017;Galdino et al, 2018). It has been shown, that zymosan (predominantly composed of β1,3 glucan) can induce anti-inflammatory effects on T cell differentiation and promote the generation of regulatory T cells (Caminschi et al, 2019;Dillon et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

et al. 2020

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Priming at the site of natural infection typically elicits a protective T cell response against subsequent pathogen encounter. Here, we report the identification of a novel fungal antigen that we harnessed for mucosal vaccination and tetramer generation to test whether we can elicit protective, antigen-specific tissue resident memory (Trm) CD4 + T cells in the lung parenchyma. In contrast to expectations, CD69 + , CXCR3 + , CD103 − Trm cells failed to protect against a lethal pulmonary fungal infection. Surprisingly, systemic vaccination induced a population of tetramer + CD4 + T cells enriched within the pulmonary vasculature, and expressing CXCR3 and CX3CR1, that migrated to the lung tissue upon challenge and efficiently protected mice against infection. Mucosal vaccine priming of Trm may not reliably protect against mucosal pathogens.

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Section: Discussionmentioning

confidence: 99%

Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

et al. 2020

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“…10, 38,39 Th17 and Treg cells always play opposing roles in fungal infection. 12,27,40 An impaired balance of Th17/Treg is associated with disease progression, while the inhibition or depletion of Treg cells could potentially rescue Th1/Th17 immunity and improve prognosis. 12,27,40 Foxp3 could inhibit RORγt and down-regulate the expression of RORγt-mediated IL-17.…”

Section: Discussionmentioning

confidence: 99%

“…12,27,40 An impaired balance of Th17/Treg is associated with disease progression, while the inhibition or depletion of Treg cells could potentially rescue Th1/Th17 immunity and improve prognosis. 12,27,40 Foxp3 could inhibit RORγt and down-regulate the expression of RORγt-mediated IL-17. 41 Therefore, the dominance of Treg cells could be associated with the down-regulation of RORγt expression and the suppression of Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

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<p>Dendritic Cells Promote Treg Expansion but Not Th17 Generation in Response to <em>Talaromyces marneffei</em> Yeast Cells</p>

Tang¹,

Zhang²,

Xu³

et al. 2020

IDR

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These authors contributed equally to this work 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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“…Our previous studies have shown that Treg cells can be protective or deleterious to P. brasiliensis infected mice 34,35,67,68 . At all post-infection times assayed, a reduced presence of Treg cells was here observed in line with reduced Foxp3 mRNA detected and the low levels of IL-10, TGF-β and IL-35, cytokines involved in the suppressive activity of this T cell subpopulation.…”

Section: Scientific Reports |mentioning

confidence: 99%

Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

Araújo

Preite

Veldhoen

et al. 2020

Sci Rep

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AhR is a ligand-activated transcription factor that plays an important role in the innate and adaptive immune responses. In infection models, it has been associated with host responses that promote or inhibit disease progression. In pulmonary paracoccidioidomycosis, a primary fungal infection endemic in Latin America, immune protection is mediated by Th1/Th17 cells and disease severity with predominant Th2/Th9/Treg responses. Because of its important role at epithelial barriers, we evaluate the role of AhR in the outcome of a pulmonary model of paracoccidioidomycosis. AhR −/− mice show increased fungal burdens, enhanced tissue pathology and mortality. During the infection, AhR −/− mice have more pulmonary myeloid cells with activated phenotype and reduced numbers expressing indoleamine 2,3 dioxygenase 1. AhR-deficient lungs have altered production of cytokines and reduced numbers of innate lymphoid cells (NK, ILC3 and NCR IL-22). The lungs of AhR −/− mice showed increased presence Th17 cells concomitant with reduced numbers of Th1, Th22 and Foxp3 + Treg cells. Furthermore, treatment of infected WT mice with an AhR-specific antagonist (CH223191) reproduced the main findings obtained in AhR −/− mice. Collectively our data demonstrate that in pulmonary paracoccidioidomycosis AhR controls fungal burden and excessive tissue inflammation and is a possible target for antifungal therapy. AhR is a ligand-activated cytosolic transcription factor with known involvement in the metabolism of xenobiotic compounds. It mediates the toxic effects of man-made aryl hydrocarbons including 2,3,7,8-tetrachlorodibenzenop-dioxin (also known as TCDD or Dioxin) 1 but can also be activated by a diverse set of endogenous and exogenous ligands 2. In steady state, AhR remains in the cytoplasm as part of an inactive complex composed of several chaperone proteins 3. Upon ligand binding, AhR is released, translocate to the nucleus and heterodimerizes with its partner AhR Nuclear Translocator (ARNT). The heterodimer can bind genomic regions containing its binding motif, thereby inducing the transcription of target genes including detoxifying enzymes of the cytochrome P 450 family 4 and the AhR repressor that disrupts the AhR/ARNT complex and attenuates AhR signaling. In the nucleus, AhR can interact with several transcription factors that regulate its activity 3. The degree of AhR activation may dependent on the structure and receptor affinity of the ligand. Several tryptophan (Trp) degradation products such as Kynurenine (Kyn), produced by the enzymatic action of indoleamine 2,3 dioxygenase (IDO-1) and 6-formylindolo[3,2-b] carbazole (FICZ), a tryptophan condensation product, are well known AhR ligands 5,6. AhR is expressed by cells of the innate and adaptive immune system and participates in the control of cell proliferation, differentiation and cytokine secretion 6-10. In 2008, different laboratories showed that AhR contributes to the differentiation of Th17 and regulatory T cells (Treg) 8-10. Interestingly, two different AhR ligands (TCDD and...

show abstract

Depletion of regulatory T cells in ongoing paracoccidioidomycosis rescues protective Th1/Th17 immunity and prevents fatal disease outcome

Cited by 28 publications

References 63 publications

Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

<p>Dendritic Cells Promote Treg Expansion but Not Th17 Generation in Response to <em>Talaromyces marneffei</em> Yeast Cells</p>

Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

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