Alternatively activated monocyte-derived myeloid cells promote extracellular pathogen persistence within pulmonary fungal granulomas

Inhaled fungal pathogens often generate granuloma-contained latent infections that can reactivate to cause invasive disease. However, the mechanisms underlying the inability to generate sterilizing immunity against latent infection remains poorly understood. Here, we leveraged spatial transcriptomics and flow cytometry to characterize the immune dynamics and cellular architecture of cryptococcal granulomas. Using fate mapping and murine genetic tools, we demonstrate that alternative activation of monocyte-derived myeloid cells by CD4 ⁺ T helper 2 cells antagonizes pulmonary fungal clearance during latent infection. In contrast to the prevailing view in the field, we find that alternatively activated myeloid cells are not an intrinsic replication niche for the fungus and more broadly, Cryptococcus predominantly resides in the extracellular environment. We propose a T helper 2 cell-myeloid circuit establishes a local immunosuppressive environment to drive extracellular fungal persistence, which could be leveraged as a new target for host-directed therapy to treat latent fungal infections.