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

ABSTRACT: In human paracoccidioidomycosis (PCM), a primary fungal infection typically diagnosed when the disease is already established, regulatory T cells (Treg) cells are associated with disease severity. Experimental studies in pulmonary PCM confirmed the detrimental role of these cells, but in most studies, Tregs were depleted prior to or early during infection. These facts led us to study the effects of Treg cell depletion using a model of ongoing PCM. Therefore, Treg cell depletion was achieved by treatment of transgenic C57BL/6^DTR/eGFP (DEREG) mice with diphtheria toxin (DT) after 3 weeks of intratracheal infection with 1?×?10⁶ Paracoccidioides brasiliensis yeasts. At weeks 6 and 10 post-infection, DT-treated DEREG mice showed a reduced number of Treg cells associated with decreased fungal burdens in the lungs, liver and spleen, reduced tissue pathology and mortality. Additionally, an increased influx of activated CD4⁺ and CD8⁺ T cells into the lungs and elevated production of Th1/Th17 cytokines was observed in DT-treated mice. Altogether, our data demonstrate for the first time that Treg cell depletion in ongoing PCM rescues infected hosts from progressive and potentially fatal PCM; furthermore, our data indicate that controlling Treg cells could be explored as a novel immunotherapeutic procedure.

SUBMITTER: Galdino NAL

PROVIDER: S-EPMC6224548 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Galdino Nayane A L NAL Loures Flávio V FV de Araújo Eliseu F EF da Costa Tania A TA Preite Nycolas W NW Calich Vera Lúcia G VLG

Scientific reports 20181108 1

In human paracoccidioidomycosis (PCM), a primary fungal infection typically diagnosed when the disease is already established, regulatory T cells (Treg) cells are associated with disease severity. Experimental studies in pulmonary PCM confirmed the detrimental role of these cells, but in most studies, Tregs were depleted prior to or early during infection. These facts led us to study the effects of Treg cell depletion using a model of ongoing PCM. Therefore, Treg cell depletion was achieved by t ...[more]

PMID: 30410119

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Project description:We previously reported interferon gamma secretion by human CD4? and CD8? T cells in response to recombinant E. coli-expressed Rv1860 protein of Mycobacterium tuberculosis (MTB) as well as protection of guinea pigs against a challenge with virulent MTB following prime-boost immunization with DNA vaccine and poxvirus expressing Rv1860. In contrast, a Statens Serum Institute Mycobacterium bovis BCG (BCG-SSI) recombinant expressing MTB Rv1860 (BCG-TB1860) showed loss of protective ability compared to the parent BCG strain expressing the control GFP protein (BCG-GFP). Since Rv1860 is a secreted mannosylated protein of MTB and BCG, we investigated the effect of BCG-TB1860 on innate immunity. Relative to BCG-GFP, BCG-TB1860 effected a significant near total reduction both in secretion of cytokines IL-2, IL-12p40, IL-12p70, TNF-?, IL-6 and IL-10, and up regulation of co-stimulatory molecules MHC-II, CD40, CD54, CD80 and CD86 by infected bone marrow derived dendritic cells (BMDC), while leaving secreted levels of TGF-? unchanged. These effects were mimicked by BCG-TB1860His which carried a 6-Histidine tag at the C-terminus of Rv1860, killed sonicated preparations of BCG-TB1860 and purified H37Rv-derived Rv1860 glycoprotein added to BCG-GFP, but not by E. coli-expressed recombinant Rv1860. Most importantly, BMDC exposed to BCG-TB1860 failed to polarize allogeneic as well as syngeneic T cells to secrete IFN-? and IL-17 relative to BCG-GFP. Splenocytes from mice infected with BCG-SSI showed significantly less proliferation and secretion of IL-2, IFN-? and IL-17, but secreted higher levels of IL-10 in response to in vitro restimulation with BCG-TB1860 compared to BCG-GFP. Spleens from mice infected with BCG-TB1860 also harboured significantly fewer DC expressing MHC-II, IL-12, IL-2 and TNF-? compared to mice infected with BCG-GFP. Glycoproteins of MTB, through their deleterious effects on DC may thus contribute to suppress the generation of a TH1- and TH17-dominated adaptive immune response that is vital for protection against tuberculosis.

Dataset Information

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

Publications

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

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