Lung CD4 resident memory T cells use airway secretory cells to stimulate and regulate onset of allergic airway neutrophilic disease.

Neutrophilic asthma is a vexing disease, but mechanistic and therapeutic advancements will require better models of allergy-induced airway neutrophilia. Here, we find that periodic ovalbumin (OVA) inhalation in sensitized mice elicits rapid allergic airway inflammation and pathophysiology mimicking neutrophilic asthma. OVA-experienced murine lungs harbor diverse clusters of CD4 resident memory T (T) cells, including unconventional RORγt T helper 17 (T17) cells. Acute OVA challenge instigates interleukin (IL)-17A secretion from these T cells, driving CXCL5 production from Muc5ac airway secretory cells, leading to destructive airway neutrophilia. The T and epithelial cell signals discovered herein are also observed in adult human asthmatic airways. Epithelial antigen presentation regulates this biology by skewing T cells toward T2 and T1 fates so that T1-related interferon (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 cell crosstalk as a key rheostat of allergic airway neutrophilia.