Type 1 conventional dendritic cells regulate innate immunity during fungal pneumonia

Area of Science:

• Immunology
• Infectious Diseases
• Mycology

Background:

• Invasive pulmonary aspergillosis (IPA), caused by Aspergillus fumigatus, is a severe lung infection with high mortality in immunocompromised individuals.
• Innate immunity, particularly dendritic cells (DCs), plays a critical role in controlling IPA severity.
• While monocyte-derived DCs and plasmacytoid DCs show protective roles, the function of type 1 conventional dendritic cells (cDC1s) in IPA remains unclear.

Purpose of the Study:

• To investigate the role of type 1 conventional dendritic cells (cDC1s) in the host immune response to Aspergillus fumigatus lung infection.
• To determine if cDC1s contribute to or hinder the clearance of A. fumigatus during invasive pulmonary aspergillosis.

Main Methods:

• Utilized three distinct mouse models deficient in cDC1s (Batf3-/- , Cd11cCre/Irf8flox/flox , and interferon regulatory factor 8 +32-/- mice) to assess fungal clearance.
• Analyzed immune responses, including type 17 immunity, IL-33, and PGE2 production, in cDC1-deficient mice.
• Evaluated the fungicidal activity of alveolar macrophages from cDC1-deficient mice and in co-culture with bone marrow-derived cDC1s.

Main Results:

• Mice lacking cDC1s exhibited enhanced clearance of Aspergillus fumigatus from the lungs compared to wild-type controls.
• cDC1-deficient mice showed an augmented type 17 immune response, correlated with altered IL-33 and PGE2 levels.
• Alveolar macrophages from cDC1-deficient mice displayed increased fungicidal activity, suggesting cDC1s restrict macrophage function.

Conclusions:

• Type 1 conventional dendritic cells (cDC1s) negatively regulate innate immune responses and hinder the clearance of Aspergillus fumigatus during invasive pulmonary aspergillosis.
• cDC1s restrict the fungicidal activity of alveolar macrophages and modulate type 17 immune responses.
• These findings identify cDC1s as a novel regulatory mechanism impacting host defense during IPA.