ABSTRACT

Neutrophilic asthma is a vexing disease, but mechanistic and therapeutic advancement will require better models of allergy-induced airway neutrophilia. Here, we find that periodic ovalbumin (OVA) inhalation in sensitized mice elicits allergic airway inflammation and pathophysiology mimicking neutrophilic asthma. OVA-experienced murine lungs harbor diverse clusters of CD4 + resident memory T RM cells, including unconventional RORγt negative/low T H 17 cells. Acute OVA challenge instigates IL-17A secretion from these T RM cells, driving CXCL5 production from Muc5ac high airway secretory cells, leading to destructive airway neutrophilia. The T RM - and epithelial-cell signals discovered herein are also observed in adult human asthmatic airways. Epithelial antigen presentation regulates this biology by skewing T RM cells towards T H 2 and T H 1 fates, so that the T H 1-related IFN-γ suppresses IL-17A-driven, CXCL5-mediated airway neutrophilia. Concordantly, in vivo IFN-γ supplementation improves disease outcomes. Thus, using our model of neutrophilic asthma we identify lung epithelial-CD4 + T RM cell crosstalk as a key rheostat of allergic airway neutrophilia.

Highlights

Recurrent OVA inhalation experience predisposes mice to allergic airways neutrophilia Neutrophil-prone lungs harbor CD4 + T RM cells including RORγt negative/low T H 17 cells Muc5ac high secretory cells instruct CD4 + T RM fates and neutrophilia via MHC-II and CXCL5, respectively Prophylactic or therapeutic delivery of IFN-γ curbs allergic airway neutrophilia