Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching

Invasive pulmonary aspergillosis is a lethal opportunistic fungal infection in transplant recipients receiving calcineurin inhibitors. We previously identified a role for the calcineurin pathway in innate immune responses to <i>A. fumigatus</i> and have used exogenous interferon-gamma successfully to treat aspergillosis in this setting. Here we show that calcineurin inhibitors block dendritic cell maturation in response to <i>A. fumigatus,</i> impairing the Th1 polarization of CD4 cells. Interferon gamma, an immunotherapeutic option for invasive aspergillosis, restored maturation and promoted Th1 polarization via a dendritic cell dependent effect that was co-dependent on T cell interaction. We find that interferon gamma activates alternative transcriptional pathways to calcineurin-NFAT for the augmentation of pathogen handling. Histone modification ChIP-Seq analysis revealed dominant control by an interferon gamma induced regulatory switch from STAT3 to STAT1 transcription factor binding underpinning these observations. These findings provide key insight into the mechanisms of immunotherapy in organ transplant recipients with invasive fungal diseases.