The Proximal Airway Is a Reservoir for Adaptive Immunologic Memory in Idiopathic Subglottic Stenosis

Objectives/Hypothesis: Characterization of the localized adaptive immune response in the airway scar of patients with idiopathic subglottic stenosis (iSGS). Study Design: Basic Science. Methods: Utilizing 36 patients with subglottic stenosis (25 idiopathic subglottic stenosis [iSGS], 10 iatrogenic post-intubation stenosis [iLTS], and one granulomatosis with polyangiitis [GPA]) we applied immunohistochemical and immunologic techniques coupled with RNA sequencing. Results: iSGS, iLTS, and GPA demonstrate a significant immune infiltrate in the subglottic scar consisting of adaptive cell subsets (T cells along with dendritic cells). Interrogation of T cell subtypes showed significantly more CD69⁺ CD103⁺ CD8⁺ tissue resident memory T cells (T_RM) in the iSGS airway scar than iLTS specimens (iSGS vs. iLTS; 50% vs. 28%, P =.0065). Additionally, subglottic CD8⁺ clones possessed T-cell receptor (TCR) sequences with known antigen specificity for viral and intracellular pathogens. Conclusions: The human subglottis is significantly enriched for CD8⁺ tissue resident memory T cells in iSGS, which possess TCR sequences proven to recognize viral and intracellular pathogens. These results inform our understanding of iSGS, provide a direction for future discovery, and demonstrate immunologic function in the human proximal airway. Laryngoscope, 131:610–617, 2021.