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

Inhaled fungal pathogens often generate granuloma-contained latent infections that can reactivate to cause invasive disease. However, why protective pathways fail to achieve sterilizing immunity in this setting is unclear. Here, we identify type 2 inflammation as a major arm of immunosuppression during latent, granulomatous fungal infection. Using reporter mice, we found that TH2 cells were the dominant source of type 2 cytokines and deletion of IL-4/IL-13, Stat6, or TH2 cells drove fungal clearance. Type 2 signaling acted on monocyte-derived myeloid cells that formed an ARG1+ ring around the granuloma core. STAT6 was required cell intrinsically in this compartment, and its loss reduced lung burden. Contrary to an intracellular-niche model, we found that Cryptococcus was predominantly extracellular in vivo. STAT6 deficiency did not enhance macrophage intracellular killing, but instead antagonized IFNγ-dependent protection against extracellular yeast. These findings identify a spatially organized TH2-STAT6 checkpoint that limits IFNγ-mediated extracellular killing and maintains cryptococcal latency.