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(RM)) cells, including unconventional RORγt(negative/low) T helper 17 (T(H)17) cells. Acute OVA challenge instigates interleukin (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 toward T(H)2 and T(H)1 fates so that T(H)1-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(RM) cell crosstalk as a key rheostat of allergic airway neutrophilia.