Clonotypic Insulation And Microbiome-Associated Filtering Define The Human Airway T Cell Repertoire

Tissue-resident immunity in the human lung is often inferred from circulating immune profiles, yet the organizational principles governing airway T cell receptor (TCR) repertoires remain poorly defined. Using TRUST4-based reconstruction of TCR repertoires from bulk RNA sequencing of matched peripheral blood, bronchoalveolar lavage (BAL), and induced sputum samples, we define the structural logic of human airway T cell immunity. Across all TCR chains, airway repertoires were clonotypically insulated from circulation, exhibiting minimal overlap with blood despite selective sharing of high-abundance clonotypes. TCR diversity progressively contracted from blood to BAL to sputum, accompanied by increased clonal dominance, consistent with compartmental filtering along the airway axis. Stratification by HIV infection and chronic obstructive pulmonary disease (COPD) revealed modest modulation without disrupting architecture. Microbiome-TCR interaction analyses identified clonotype-specific disease modification selectively in BAL. Together, these findings establish the airway as a structurally insulated immune niche whose T cell repertoire is shaped by compartmental filtering and disease-modified microbial coupling