Crosstalk between CD4+ T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma

Rationale: Pediatric obesity-related asthma is a non-atopic asthma phenotype with high disease burden and few effective therapies. RhoGTPase upregulation in peripheral blood TH cells is associated with the phenotype but the mechanisms that underlie this association are not known. Objective: To investigate the mechanisms by which upregulation of CDC42, a RhoGTPase, in TH cells, is associated with airway smooth muscle (ASM) biology. Methods: Chemotaxis of obese asthma and healthy-weight asthma TH cells, and their adhesion to obese and healthy-weight non-asthmatic ASM, was investigated. Transcriptomics and proteomics were used to determine the differential effect of obese and healthy-weight asthma TH cell adhesion to obese or healthy-weight ASM biology. Measurement and Main Results: Chemotaxis of obese asthma TH cells with CDC42 upregulation was resistant to CDC42 inhibition. Obese asthma TH cells were more adherent to obese ASM as compared to healthy-weight asthma TH cells to healthy-weight ASM. Compared to co-culture with healthy-weight ASM, obese asthma TH cell co-culture with obese ASM was positively enriched for genes and proteins involved in actin cytoskeleton organization, transmembrane receptor protein kinase signaling, and cell mitosis, and negatively enriched for extracellular matrix organization. Targeted gene evaluation revealed upregulation of IFNG, TNF and CD247 among TH cell genes, and of AKT, RHOA and CD38, with downregulation of PKCA, among smooth muscle genes. Conclusions: Obese asthma TH cells have uninhibited chemotaxis and are more adherent to obese ASM, which is associated with upregulation of genes and proteins associated with smooth muscle proliferation and reciprocal non-atopic TH cell activation.