Ravi VR, Korkmaz FT, De Ana CL, Lu L, Shao FZ, Odom CV, Barker KA, Ramanujan A, Niszczak EN, Goltry WN, Martin IMC, Ha CT, Quinton LJ, Jones MR, Fine A, Welch JD, Chen F, Belkina AC, Mizgerd JP, Shenoy AT. Cell Rep. 2025 Feb 11:115294. doi: 10.1016/j.celrep.2025.115294.

Highlights

• Recurrent OVA inhalation experience predisposes mice to rapid allergic airway neutrophilia
• Neutrophil-prone allergic lungs harbor CD4⁺ T_RM cells, including RORγt^negative/low T_H17 cells
• Muc5ac^high secretory cells instruct CD4⁺ T_RM fates and neutrophilia via MHC class II and CXCL5
• Prophylactic or therapeutic delivery of IFN-γ curbs allergic airway neutrophilia

Summary

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_H17) 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_H2 and T_H1 fates so that T_H1-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.

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