EARLY OR LATE IL-10 BLOCKADE ENHANCES TH1 AND TH17 EFFECTOR RESPONSES AND PROMOTES FUNGAL CLEARANCE IN MICE WITH CRYPTOCOCCAL LUNG INFECTION1

The potent immunoregulatory properties of Interleukin-10 (IL-10) can counteract protective immune responses and thereby promote persistent infections as evidenced by prior studies of cryptococcal lung infection in IL-10 deficient mice. To further investigate how IL-10 impairs fungal clearance the current study utilized an established murine model of C57BL/6 mice infected with C. neoformans strain 52D. Our results demonstrate that fungal persistence is associated with an early and sustained expression of IL-10 by lung leukocytes. To examine whether IL-10-mediated immune modulation occurs during the early or late phase of infection, assessments of fungal burden and immunophenotyping were performed on mice treated with anti-IL-10 receptor blocking antibody at 3, 6, and 9 days post-infection (dpi) (early phase) or at 15, 18, and 21 dpi (late phase). We found that both early and late IL-10 blockade significantly improved fungal clearance within the lung when assessed 35 dpi compared to isotype control treatment. Immunophenotyping identified that IL-10 blockade enhanced several critical effector mechanisms including: a) increased accumulation of CD4+ T cells and B cells, but not CD8+ T cells, b) specific increases in the total numbers of Th1 and Th17 cells, and c) increased accumulation and activation of CD11b+ dendritic cells and exudate macrophages. Importantly, IL-10 blockade effectively abrogated dissemination of C. neoformans to the brain. Collectively, this study identifies early and late cellular and molecular mechanisms through which IL-10 impairs fungal clearance and highlights the therapeutic potential of IL-10 blockade in the treatment of fungal lung infections.