Compartment-specific phase compensation between pulmonary T-Cell immunity and waning systemic responses in BA.5 breakthrough infection

Spatiotemporal coordination of SARS-CoV-2-specific immunity across pulmonary and systemic compartments is poorly defined, especially how chronic lung diseases modulate this. We hypothesized that profiling virus-specific T cells (VSTs) and antibodies in respiratory vs. blood samples would reveal compartmentalized dynamics critical for viral control. In 64 mild Omicron BA.5 breakthrough-infected participants (30 early D7, 34 later D14), we performed: 1) Paired sputum/PBMCs flow cytometry for CD4⁺/CD8⁺ VSTs; 2) Systemic antibody titration (NAbs, anti-N IgG); 3) Compartmental cytokine profiling; 4) Stratified analysis of GOLD I-II COPD (n = 28) vs controls (n = 36). Pulmonary CD4⁺ VSTs increased 2.8-fold from D7 to D14, contrasting with delayed CD8⁺ VSTs mobilisation, while no sputum-blood VSTs correlations existed in either phase (all P > 0.05). Phase-dependent immune synergy was observed in that early viral control was driven by blood CD8⁺ VSTs-NAbs coordination (CT value: r = 0.43; NAbs: r = 0.41; both P 0.05). Non-invasive sputum analysis reveals dynamic SARS-CoV-2 immunity: systemic effectors dominate early control, while pulmonary CD4⁺ VSTs compensate during antibody decline, underscoring the need for phase-specific therapeutic regimens targeting distinct compartments.