Depletion of regulatoryT cells in ongoing paracoccidioidomycosis rescues protective Thl/Th17 immunity and prevents fatal disease outcome

In human paracoccidioidomycosis (PCM), a primary fungal infection typically diagnosed when the disease is already established, regulatoryT cells (Treg) cells are associated with disease severity. Experimental studies in pulmonary PCM confirmed the detrimental role of these cells, but in most studies, Tregs were depleted prior to or early during infection. These facts led us to study the effects of Treg cell depletion using a model of ongoing PCM. Therefore, Treg cell depletion was achieved by treatment of transgenic C57BL/6(DTR/eGFP) (DEREG) mice with diphtheria toxin (DT) after 3 weeks of intratracheal infection with 1 x 10(6) Paracoccidioides brasiliensis yeasts. At weeks 6 and 10 post infection, DT-treated DEREG mice showed a reduced number of Treg cells associated with decreased fungal burdens in the lungs, liver and spleen, reduced tissue pathology and mortality. Additionally, an increased influx of activated CD4(+) and CD8(+) T cells into the lungs and elevated production of Thl/ Th17 cytokines was observed in DT-treated mice. Altogether, our data demonstrate for the first time that Treg cell depletion in ongoing PCM rescues infected hosts from progressive and potentially fatal PCM; furthermore, our data indicate that controlling Treg cells could be explored as a novel immunotherapeutic procedure. (AU)