ABSTRACTAspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure toA. fumigatusconidia. C57BL/6 mice were challenged intranasally withA. fumigatusconidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% ofA. fumigatusconidia were cleared within 24 h after inoculation, and repeated exposure toA. fumigatusconidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (Treg) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continuedA. fumigatuschallenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure toA. fumigatusconidia induced T cell activation in the lungs and the codevelopment by four exposures of TH1, TH2, and TH17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or Tregnumbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure toA. fumigatusconidia.
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