Type 1 conventional dendritic cells regulate innate immunity during fungal pneumonia

Aspergillus fumigatus is a ubiquitous mold that is the primary etiological agent of invasive pulmonary aspergillosis (IPA), a severe lung infection in immunocompromised patients with extreme mortality. Innate immunity is critical for controlling the severity of IPA. Regarding dendritic cells (DCs), studies have shown protective roles for monocyte-derived DCs and plasmacytoid DCs during IPA. Here, we examined the role of type 1 conventional dendritic cells (cDC1s) during A. fumigatus lung infection. We first show that global depletion of DCs resulted in impaired lung clearance of A. fumigatus, indicating a protective role for DCs, as expected. Unexpectedly, however, mice lacking cDC1s (Batf3-/-) cleared A. fumigatus more efficiently than wild-type C57BL/6 control mice. Enhanced fungal clearance was also observed in two additional cDC1-deficient strains, Cd11cCre/Irf8flox/flox mice and interferon regulatory factor 8 +32-/- mice. Batf3-/- mice displayed an enhanced type 17 immune response, which we have shown to be required for optimal immunity during IPA. Moreover, elevated type 17 responses correlated with differential production of IL-33 (decreased in Batf3-/-) and PGE2 (increased in Batf3-/-), an axis we have reported to promote type 17 responses during IPA. We further show that alveolar macrophages from Batf3-/- mice had increased fungicidal activity against A. fumigatus. In contrast, alveolar macrophages cultured in the presence of bone marrow-derived cDC1s had lower fungicidal activity compared to alveolar macrophages cultured alone, suggesting that cDC1s restrict alveolar macrophage function. Taken together, our data identify cDC1s as a regulator of innate immune responsiveness during IPA.IMPORTANCEFungal infections have increased at an alarming rate as a result of increased usage of immunosuppressive therapies, growing resistance to antifungal drugs, and global warming. This recently prompted the World Health Organization to publish the first-ever fungal priority pathogens list, which focused on 19 organisms, ultimately deeming 4 pathogens of critical importance based on perceived public health importance. Among these four was the opportunistic mold Aspergillus fumigatus, the etiological agent of the most lethal fungal infection known to humans, IPA. Innate immunity is paramount for controlling IPA with protective roles identified for multiple myeloid cell types. In the current report, employing three complementary animal models, we show that cDC1s hinder the clearance of A. fumigatus from the lung. We further identified specific responses that are regulated by cDC1s. Overall, our study uncovers a new mechanism of immune regulation during IPA.