Tolerogenic Plasmacytoid Dendritic Cells Control Paracoccidioides brasiliensis Infection by Inducting Regulatory T Cells in an IDO-Dependent Manner

Abstract

Plasmacytoid dendritic cells (pDCs), considered critical for immunity against viruses, were recently associated with defense mechanisms against fungal infections. However, the immunomodulatory function of pDCs in pulmonary paracoccidiodomycosis (PCM), an endemic fungal infection of Latin America, has been poorly defined. Here, we investigated the role of pDCs in the pathogenesis of PCM caused by the infection of 129Sv mice with 1 x 106 P. brasiliensis-yeasts. In vitro experiments showed that P. brasiliensis infection induces the maturation of pDCs and elevated synthesis of TNF-α and IFN-β. The in vivo infection caused a significant influx of pDCs to the lungs and increased levels of pulmonary type I IFN. Depletion of pDCs by a specific monoclonal antibody resulted in a less severe infection, reduced tissue pathology and increased survival time of infected mice. An increased influx of macrophages and neutrophils and elevated presence of CD4+ and CD8+ T lymphocytes expressing IFN-γ and IL-17 in the lungs of pDC-depleted mice were also observed. These findings were concomitant with decreased frequency of Treg cells and reduced levels of immunoregulatory cytokines such as IL-10, TGF-β, IL-27 and IL-35. Importantly, P. brasilienis infection increased the numbers of pulmonary pDCs expressing indoleamine 2,3-dioxygenase-1 (IDO), an enzyme with immunoregulatory properties, that were reduced following pDC depletion. In agreement, an increased immunogenic activity of infected pDCs was observed when IDO-deficient or IDO-inhibited pDCs were employed in co-cultures with lymphocytes Altogether, our results suggest that in pulmonary PCM pDCs exert a tolerogenic function by an IDO-mediated mechanism that increases Treg activity.

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

“…Unstimulated or alternatively activated pDCs are able to induce T cell tolerance to tumor cells, harmless antigens and alloantigens, primarily through the induction of regulatory T cells (Tregs) [109][110][111][112]. pDCs induce tolerance by expressing indoleamine 2,3-dioxygenase (IDO) [113][114][115], inducible T cell costimulator ligand (ICOSL) [109], tumor necrosis factor ligand superfamily member 4 (TNFSF4; also known as OX40L) [116,117], PD-L1 [118] or GrB [119]. It has been reported that a fraction of pDCs found in tumor draining lymph nodes (TDLNs) express IDO and activate Tregs [113,115].…”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…For instance, lymphoid-derived plasmacytoid DCs (pDCs) have been suggested to have a role in antifungal immunity in a tissue-dependent manner. Whereas depletion of pDCs was shown to render mice more susceptible to invasive aspergillosis in one study [112], others have suggested that pDCs can mediate tolerance in vaginal candidiasis and in a model of lung infection with P. brasiliensis [113]. P. brasiliensis infection, for example, increased the number of pDCs expressing indoleamine 2,3-dioxygenase (IDO), an enzyme with immunoregulatory properties that drives regulatory T cell (T reg ) expansion [113].…”

“…Whereas depletion of pDCs was shown to render mice more susceptible to invasive aspergillosis in one study [112], others have suggested that pDCs can mediate tolerance in vaginal candidiasis and in a model of lung infection with P. brasiliensis [113]. P. brasiliensis infection, for example, increased the number of pDCs expressing indoleamine 2,3-dioxygenase (IDO), an enzyme with immunoregulatory properties that drives regulatory T cell (T reg ) expansion [113]. Remarkably, dectin-1-mediated activation of pDCs has been suggested to promote Th2 responses, while dectin-1 activation on myeloid DCs decrease Th2 responses upon β-glucan challenge.…”

Regulatory T cells in paracoccidioidomycosis

“…Furthermore, a reduced number of Foxp3 + Treg cells and decreased presence of pDCs expressing IDO were found in the lungs of pDC-depleted mice. Strong evidence for the role of IDO expression in the expansion of Treg cells was obtained using an in vitro experiment: pDCs of IDO-deficient mice and 1MT-treated pDCs of WT mice stimulated by P. brasiliensis yeast were more efficient at the induction and activation of T cells with concomitant reduction of Treg cells [121]. No surprises came out when we further explored the regulatory mechanism exerted by IDO-1 in the early and late phases of immunity against P. brasiliensis infection using IDO-1 −/mice.…”

“…This type of immunity is the worst scenario for a host response to a pathogen, where uncontrolled fungal growth is accompanied by intense but inefficient inflammatory reactions causing exaggerated tissue pathology that ultimately leads to the accelerated death of infected mice [122]. Both studies showed that the IDO/ Treg/Th17 axis plays important roles in the control of immunity and the severity of pulmonary PCM [121,122].…”