Whole‐blood CD3 / CD28 ‐stimulated cytokine responses in children with preschool wheeze, asthma, and healthy controls

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BACKGROUND: Childhood asthma and wheezing disorders are heterogeneous conditions that may be reflected by distinct immune response patterns. In this study, we investigated whether CD3/CD28-stimulated cytokine responses differ between children with asthma, preschool wheeze, and healthy controls. METHODS: Baseline samples from 511 children in the All Age Asthma cohort (ALLIANCE; 196 children with asthma, 181 with preschool wheeze, and 134 healthy controls) were analyzed. Whole blood was stimulated with anti-CD3/CD28 antibodies for 48 h, and 37 cytokines were quantified using multiplex immunoassays. Cytokine co-variation patterns were assessed using principal component analysis (PCA). Co-regulated cytokine modules were identified using CytoMod, and associations with clinical characteristics were examined using linear and logistic regression models. RESULTS: Two cytokines, sCD30 and sCD163, showed significant age-related decreases (β = -.07 (95% CI -0.09 to -0.06), padj = 1.2e-14; and β = -.03 (95% CI -0.04 to -0.01), padj = .018, respectively). After correction for multiple testing, no individual cytokine differed significantly between children with asthma, preschool wheeze, or healthy controls. PCA demonstrated highly conserved cytokine co-variation patterns across groups (Spearman's rho >.9 for the first principal component loadings). Modular analysis identified six distinct co-regulatory modules after adjustment for background cytokine levels. Associations between module expression and clinical characteristics were generally modest. Module 1, comprising cytokines associated with tissue remodeling and IL-6 signaling, was inversely associated with asthma in children aged ≥6 years (OR = 0.63 (95% CI 0.46-0.85), padj = .017). However, this association attenuated in age-matched sensitivity analyses (OR = 0.72 (95% CI 0.51-0.99), padj = .281), suggesting residual age-related confounding. CONCLUSIONS: CD3/CD28-stimulated cytokine responses show highly conserved T-cell activation networks across pediatric asthma, preschool wheeze, and health, with limited ability to distinguish between clinical groups at the single-cytokine level. Nevertheless, modular network analyses identify coordinated immune patterns associated with clinical features, highlighting the potential value of immune profiling in refining biological phenotyping and advancing the understanding of immune heterogeneity in pediatric airway disease.

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