Type 1 conventional dendritic cells (cDC1s) negatively regulate innate immunity during fungal pneumonia 3273

Abstract Description Aspergillus fumigatus is a ubiquitous mold that can cause invasive pulmonary aspergillosis (IPA), a lung infection in immunocompromised patients with extreme mortality. While innate immunity is critical for controlling IPA, the role of dendritic cell (DC) subsets in the immune response against A. fumigatus remains unclear. Our study revealed that global depletion of DCs impaired lung clearance of A. fumigatus, indicating a protective role for DCs overall. However, mice lacking type 1 conventional DCs (cDC1s, Batf3-/- mice) cleared A. fumigatus more efficiently compared to controls. Batf3-/- mice displayed an enhanced type 17 immune response, which we have previously reported to be required for immunity during IPA. Moreover, we showed that elevated type 17 responses correlated with differential production off IL-33 and PGE2, an axis critical for type 17 responses during IPA. This non protective phenotype was replicated in another cDC1 knockout model (Irf8+ 32-/-). We also found that alveolar macrophages (AMs) from Batf3-/- mice showed increased fungicidal activity against A. fumigatus, suggesting that cDC1s may also function in restricting the activation of specific innate immune cells. In turn, we show that AMs cultured with cDC1s derived from bone marrow have reduced fungicidal activity against A. fumigatus. These findings suggest cDC1s play a regulatory role during the innate immune response to A. fumigatus in the lungs by modulating macrophage function and type 17 immunity Funding Sources NIH RO1 HL122426 NIH RO1 HL136211 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)