Myeloid-derived suppressor cells are associated with impaired Th1 and Th17 responses and severe pulmonary paracoccidioidomycosis which is reversed by anti-Gr1 therapy

Abstract

Previous studies on paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that host immunity is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO-1), and regulatory T-cells (Tregs). IDO-1 orchestrates local and systemic immunosuppressive effects through the recruitment and activation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells possessing a potent ability to suppress T-cell responses. However, the involvement of MDSCs in PCM remains uninvestigated. The presence, phenotype, and immunosuppressive activity of MDSCs were evaluated at 96 h, 2 weeks, and 8 weeks of pulmonary infection in C57BL/6 mice. Disease severity and immune responses were assessed in MDSC-depleted and nondepleted mice using an anti-Gr1 antibody. Both monocytic-like MDSCs (M-MDSCs) and polymorphonuclear-like MDSCs (PMN-MDSCs) massively infiltrated the lungs during Paracoccidioides brasiliensis infection. Partial reduction of MDSC frequency led to a robust Th1/Th17 lymphocyte response, resulting in regressive disease with a reduced fungal burden on target organs, diminishing lung pathology, and reducing mortality ratio compared with control IgG2b-treated mice. The suppressive activity of MDSCs on CD4 and CD8 T-lymphocytes and Th1/Th17 cells was also demonstrated in vitro using coculture experiments. Conversely, adoptive transfer of MDSCs to recipient P. brasiliensis-infected mice resulted in a more severe disease. Taken together, our data showed that the increased influx of MDSCs into the lungs was linked to more severe disease and impaired Th1 and Th17 protective responses. However, protective immunity was rescued by anti-Gr1 treatment, resulting in a less severe disease and controlled tissue pathology. In conclusion, MDSCs have emerged as potential target cells for the adjuvant therapy of PCM.

Transcriptional profiling of a fungal granuloma reveals a low metabolic activity of Paracoccidioides brasiliensis yeasts and an actively regulated host immune response

“…The Th17 response, although described as a crucial T cell subset in granuloma formation, it has never been described inside a chronic PCM granulomatous lesion ( Tristão et al., 2017 ). However, IL-17 expressing cells were found in the skin and mucosal lesions of patients ( Pagliari et al., 2011 ) besides a protective role of Th17 cells that has been described by our group ( Galdino et al., 2018 ; Preite et al., 2023 ). The depletion of myeloid-derived suppressor cells (MDSCs) as well as Treg cells leads to robust Th1/Th17 lymphocyte responses associated to a regressive disease with reduced fungal burden, lung pathology and mortality ratios in mice ( Galdino et al., 2018 ; Preite et al., 2023 ).…”

The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling

“…Here, we showed that the inhibition of IDO-1 by 1MT in MDSCs co-cultured with lymphocytes resulted in a higher rate of T-cell proliferation compared to untreated MDSCs. These findings suggest that, despite the activity of other immunosuppressive mechanisms in MDSCs during P. brasiliensis infection 17 , IDO-1 contributes to the suppressive activity of MDSCs. Interestingly, IDO-1 expression did not enhance MDSC differentiation or influx towards the lungs of P. brasiliensis -infected mice.…”

“…Although few studies have addressed the involvement of MDSCs in fungal infections 15 , 16 , the role of MDSCs in PCM has been recently investigated by our group. Preite et al 17 showed that MDSCs are recruited to the lungs of P. brasiliensis -infected mice and express the immunosuppressive enzyme Indoleamine 2,3 Dioxigenase-1 (IDO-1), which contributes to impaired Th1 and Th17 responses in the disease, resulting in a severe pulmonary PCM that could be reversed by MDSC depletion in mice 17 .…”

Extracellular vesicles from virulent P. brasiliensis induce TLR4 and dectin-1 expression in innate cells and promote enhanced Th1/Th17 response

“…Similarly, the characteristic immunosuppression observed in PCM patients has been associated with a high number of Treg cells expressing FoxP3 in lesions and blood [ 65 ]. Of note, the severity of PCM in mice is also affected by the action of myeloid-derived suppressor cells, which contribute to the suppressive microenvironment by producing immunosuppressive molecules and disrupting the activation of T lymphocytes [ 66 , 67 ]. Moreover, it has been described that Treg cell depletion in PCM induces a Th1/Th17 response, associated with a regressive disease with a lower fungal burden [ 68 ].…”