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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 IFN\u03b3-dependent protection against extracellular yeast. These findings identify a spatially organized TH2-STAT6 checkpoint that limits IFN\u03b3-mediated extracellular killing and maintains cryptococcal latency.<\/jats:p>","DOI":"10.1084\/jem.20260208","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T06:21:08Z","timestamp":1773469268000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Alternatively activated monocyte-derived myeloid cells promote extracellular pathogen persistence in pulmonary fungal granulomas"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4827-6191","authenticated-orcid":true,"given":"Yufan","family":"Zheng","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Mycology and Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious 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