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Background <p>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.</p> Methods <p>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 (<i>n</i> = 28) vs controls (<i>n</i> = 36).</p> Results <p>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 <i>P</i> &gt; 0.05). Phase-dependent immune synergy was observed in that early viral control was driven by blood CD8⁺ VSTs-NAbs coordination (CT value: <i>r</i> = 0.43; NAbs: <i>r</i> = 0.41; both <i>P</i> &lt; 0.05), whereas later-phase pulmonary CD4⁺ VSTs expanded reciprocally to waning systemic antibodies (NAbs: <i>r</i> = -0.54, <i>P</i> &lt; 0.01), indicating local compensation. Pulmonary cytokine dominance was evident as sputum IL-1β/IL-6/RANTES inversely correlated with viral titer (CT value) at D7 (all <i>P</i> &lt; 0.05), exhibiting stronger virological associations than their plasma counterparts. Additionally, GOLD I-II COPD patients showed no impairment in viral clearance, NAbs titres, or VSTs magnitudes versus controls (all <i>P</i> &gt; 0.05).</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Peiyu Huang,
  • Xinyue Mei,
  • Hao Xu,
  • Qi Wan,
  • Xiaohui Wu,
  • Jieqi Peng,
  • Kunning Zhou,
  • Gang Yang,
  • Li Cheng,
  • Shijun Bu,
  • Zhishan Deng,
  • Fan Wu,
  • Cuiqiong Dai,
  • Daxiang Chen,
  • Qi Luo,
  • Xi Sun,
  • Jie Su,
  • Shidong Deng,
  • Siying Wang,
  • Yufen Liu,
  • Pixin Ran,
  • Zhongfang Wang,
  • Yumin Zhou

摘要

Background

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.

Methods

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).

Results

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), whereas later-phase pulmonary CD4⁺ VSTs expanded reciprocally to waning systemic antibodies (NAbs: r = -0.54, P < 0.01), indicating local compensation. Pulmonary cytokine dominance was evident as sputum IL-1β/IL-6/RANTES inversely correlated with viral titer (CT value) at D7 (all P < 0.05), exhibiting stronger virological associations than their plasma counterparts. Additionally, GOLD I-II COPD patients showed no impairment in viral clearance, NAbs titres, or VSTs magnitudes versus controls (all P > 0.05).

Conclusions

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.