A Mixed T2/T17-Associated Systemic Immune Signature Links Airborne Pollutant Exposure to Persistent Respiratory Symptoms

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ABSTRACT Background The systemic immune responses associated with persistent respiratory symptoms (PRS) after exposure to airborne environmental pollutants remain poorly understood. Objective To identify immune disturbances associated with PRS, defined as persistent wheeze, cough, or breathlessness, we examined systemic immune responses and airway function in a cross-sectional cohort with detailed histories of airborne pollutant exposure. Methods Never-smoking post-deployment Veterans with PRS (n=16) or without PRS (n=24) underwent chest computed tomography, pulmonary function testing, and oscillometry to assess structural and functional airway abnormalities. Peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3/CD28 antibodies, lipopolysaccharide, or β-glucan, and cytokine production was measured. Correlation analyses evaluated associations between cytokine responses and physiological measures of airway function. Results Oscillometry, but not conventional pulmonary function testing or chest computed tomography, detected small-airway abnormalities in participants with PRS, including significantly greater frequency dependence of resistance and higher resonant frequency. Baseline PBMC cytokine concentrations were similar between groups. After stimulation, however, PBMCs from participants with PRS showed increased IL-17A production consistent with a type 17 (T17) response; innate stimulation also increased the type 2 (T2) cytokines IL-33 and IL-4. T2/T17 cytokine responses correlated positively with oscillometric measures of small-airway dysfunction. Conclusion Individuals with PRS exhibited a stimulus-dependent systemic T2/T17 immune signature that was associated with early small-airway dysfunction. Clinical Implication Stimulus-dependent systemic immune profiling, combined with oscillometry, may help identify early respiratory abnormalities in pollutant-exposed individuals whose conventional pulmonary tests remain normal. KEY MESSAGES Oscillometry detected early small-airway dysfunction in pollutant-exposed individuals with persistent respiratory symptoms, whereas conventional pulmonary function tests and chest CT did not distinguish the groups. Immune stimulation revealed a mixed T2/T17 systemic signature in participants with persistent respiratory symptoms, including increased IL-17A and stimulus-dependent increases in IL-4 and IL-33. T2/T17 cytokine responses correlated with oscillometric abnormalities, linking systemic immune dysregulation to small-airway dysfunction and suggesting a potential approach for identifying early pollutant-associated respiratory disease. CAPSULE SUMMARY A stimulus-dependent systemic T2/T17 immune signature correlated with oscillometric evidence of small-airway dysfunction, identifying a potential early respiratory phenotype in pollutant-exposed individuals with persistent respiratory symptoms.

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