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

作者：Vijay Raaj Ravi, F.T. Korkmaz, C. Lyon De Ana, Lu Lu, Feng-Zhi Shao, C. Odom, Kimberly A. Barker, Aditya Ramanujan, E. Niszczak, Wesley N. Goltry, Ian Martin, C. Ha, Lee J. Quinton, Matthew R. Jones, Alan Fine, Joshua D. Welch, Felicia Chen, Anna C. Belkina, Joseph P. Mizgerd, Anukul T. Shenoy · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.115294 · 被引用次数：12 · 研究领域：Asthma and respiratory diseases、IL-33, ST2, and ILC Pathways、Eosinophilic Esophagitis

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 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.