Association between IL-27 and Tr1 cells in severe form of paracoccidioidomycosis

Interleukin-27, a cytokine of the IL-12 family, is secreted by antigen-presenting cells such as macrophages and dendritic cells (DCs). Recent studies suggest an anti-inflammatory role for IL-27 by inducing IL-10 producing Tr1 cells capable of inhibiting Th1 and Th17 type responses. Our study aimed to investigate the involvement of IL-27 and Tr1 cells in the immunomodulation of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Brazil. The presence of IL-27 was evaluated in serum and biopsies of patients with PCM by ELISA, immunohistochemistry, and immunofluorescence. The presence of Tr1 in peripheral blood was analyzed by flow cytometry. In vitro assays were performed to verify the ability of P. brasiliensis yeast to induce IL-27 production by DCs and macrophages, as well as the polarization of lymphocytes to the Tr1 phenotype. Patients with the acute form and severe chronic form, the most severe and disseminated forms of PCM, presented higher serum concentrations of IL-27 and higher percentage of Tr1 cells compared to patients with mild chronic form. IL-27 was also detected in lesions of patients with PCM and associated with DCs and macrophages. P. brasiliensis Pb18 yeasts were able to induce IL-27 production by both DCs and macrophages. We found that DCs pulsed with Pb18 were able to induce Tr1 lymphocytes in vitro. Our data suggest that IL-27 and Tr1 cells could contribute to the deficient immune response to P. brasiliensis that leads to severe and disseminated forms of the disease.