Specific Depletion of Myeloid-Derived Suppressor Cells by the Chemotherapy Agent 5-Fluorouracil Enhances Protective Immune Response in Paracoccidioidomycosis

Abstract Background Paracoccidioidomycosis (PCM) is regulated by suppressive mechanisms mediated by plasmacytoid-dendritic cells, regulatory T cells and myeloid-derived suppressor cells (MDSCs). MDSC suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, ID...

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Published in:The Journal of infectious diseases 2024-07
Main Authors: Preite, Nycolas Willian, Kaminski, Valéria de Lima, Borges, Bruno Montanari, dos Santos, Bianca Vieira, Calich, Vera Lúcia Garcia, Loures, Flávio Vieira
Format: Article
Language:English
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Summary:Abstract Background Paracoccidioidomycosis (PCM) is regulated by suppressive mechanisms mediated by plasmacytoid-dendritic cells, regulatory T cells and myeloid-derived suppressor cells (MDSCs). MDSC suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, IDO-1, and PD-L1. Studies revealed the 5-fluorouracil (5-FU) as a selective MDSC apoptosis-inducing agent, but its in vivo effect on infectious processes remains poorly investigated. Methods MDSCs and other leukocytes were evaluated in the lungs of 5-FU–treated mice after 4, 6, and 8 weeks of Paracoccidioides brasiliensis infection. Disease severity and immunological response were evaluated in MDSCs-depleted mice. Results 5-FU treatment caused a reduction of pulmonary MDSCs and fungal loads. The specific depletion of MDSCs reduced all pulmonary CD4+ T-cell populations resulting in improved tissue pathology and increased survival. This reduction was concomitant with increased frequencies of Th1/Th17 cells and the increased levels of Th1/Th2/Th17 cytokines in the lungs and liver of treated mice, suggesting an early and efficient protective effect of these cells. Furthermore, the immune protection conferred by the 5-FU treatment could be reversed by the MDSC-adoptive transfer. Conclusions 5-FU depletes MDSCs of P. brasiliensis-infected mice, resulting in enhanced immunity. This protective effect can be viewed as a potential immunotherapeutic tool for PCM.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiae350