Myeloid dendritic cells (DCs) of susceptible mice to paracoccidioidomycosis suppress T cell responses whereas myeloid and plasmacytopid DCs from resistant mice induce effector and regulatory T cells

Abstract

The protective adaptive immune response in paracoccidioidomycosis, a human endemic mycosis, is mediated by T cell immunity whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived DCs of susceptible mice a prevalent pro-inflammatory myeloid phenotype that secreted high levels of IL-12, TNF-a, and IL-b, whereas in resistant mice a mixed population of myeloid and plasmacytoid DCs, secreting pro-inflammatory cytokines and expressing elevated levels of secreted and membrane-bound TGF-beta was observed. In proliferation assays, the pro-inflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and Treg cells. Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of pro-inflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded IFN-gamma+, IL-4+ and IL-17+ effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate pro-inflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis. (AU)