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

Author(s)

de Araujo, Eliseu Frank ; Medeiros, Daniella Helena ; de Lima Galdino, Nayane Alves ; Condino-Neto, Antonio ; Garcia Calich, Vera Lucia ; Loures, Flavio Vieira

• Document type: Journal article
• Source: PLOS PATHOGENS; v. 12, n. 12 DEC 2016.
• Web of Science Citations: 10

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 10(6) P. brasiliensis-yeasts. In vitro experiments showed that P. brasiliensis infection induces the maturation of pDCs and elevated synthesis of TNF-alpha and IFN-beta. 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-gamma 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-beta, 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. (AU)

• FAPESP's process: 14/18668-0 - The importance of aryl hydrocarbon receptor (AhR) in the regulation of immune response and host resistance to pulmonary paracoccidioidomycosis
• Grantee: Eliseu Frank de Araujo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/12328-6 - Type I interferons function in murine pulmonary PCM: comparative assessment of disease severity between control and knockout mice for IFN-aBR
• Grantee: Daniella Helena Medeiros
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 14/22630-9 - Study of the plasmacytoid and myeloid dendritic cells function during Paracoccidioides brasiliensis infection.
• Grantee: Flávio Vieira Loures
• Support Opportunities: Scholarships in Brazil - Young Researchers