Interferon-gamma rescues FK506 dampened dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching

Amit Adlakha et al.

IScience Highlights

Calcineurin inhibitors block DC maturation in response to A. fumigatus

Lack of DC maturation impairs Th1 polarization in response to A. fumigatus

Interferon-γ restores maturation, promotes Th1 polarization and fungal killing

ChIPseq reveals interferon-γ induces a regulatory switch from STAT3 to STAT1

Summary

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 A. fumigatus 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 A. fumigatus, impairing 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 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.

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Published
December, 2024

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