期刊
SCIENCE IMMUNOLOGY
卷 2, 期 16, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aan5357
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资金
- NIH [R01AI114647-01A1]
- Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease award
- program in Infection, Immunity and Inflammation [1T32AI125185-01]
- New Jersey Commission on Cancer Research Predoctoral Fellowship [DFHS16PPC031]
- [R01AI104669]
Type III interferons (IFN-lambda s) are the most recently found members of the IFN cytokine family and engage IFNLR1 and IL10R2 receptor subunits to activate innate responses against viruses. We have identified IFN-lambda s as critical instructors of antifungal neutrophil responses. Using Aspergillus fumigatus (Af) as a model to study antifungal immune responses, we found that depletion of CCR2(+) monocytes compromised the ability of neutrophils to control invasive fungal growth. Using an unbiased approach, we identified type I and III IFNs as critical regulators of the interplay between monocytes and neutrophils responding to Af. We found that CCR2(+) monocytes are an important early source of type I IFNs that prime optimal expression of IFN-lambda. Type III IFNs act directly on neutrophils to activate their antifungal response, and mice with neutrophil-specific deletion of IFNLR1 succumb to invasive aspergillosis. Dysfunctional neutrophil responses in CCR2-depleted mice were rescued by adoptive transfer of pulmonary CCR2(+) monocytes or by exogenous administration of IFN-alpha and IFN-lambda. Thus, CCR2(+) monocytes promote optimal activation of antifungal neutrophils by initiating a coordinated IFN response. We have identified type III IFNs as critical regulators of neutrophil activation and type I IFNs as early stimulators of IFN-lambda expression.
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