Distinct single-cell transcriptional profile in CD4+ T-lymphocytes among obese children with asthma

Obesity is a risk factor for asthma morbidity, associated with less responsiveness to inhaled corticosteroids. CD4+ T cells are central to the immunology of asthma and may contribute to the unique obese asthma phenotype. We sought to characterize the single-cell CD4+ transcriptional profile differences in obese children with asthma compared with normal-weight children with asthma. Eight normal-weight and obese participants with asthma were clinically phenotyped and matched based on asthma control. Peripheral blood (PB) CD4+ T cells were sorted, and single-cell RNA sequencing was conducted. Cell clusters were identified by canonical gene expression and differential gene expression and reactome pathway analysis was applied. The obese PB bulk transcriptomic signature from the U-BIOPRED pediatric cohort was assessed in our cohort as well. Obese children with asthma have a distinct CD4+ transcriptional profile with differential gene expression. There were more activated protein tyrosine phosphate receptor type C (PTPRC)^high cells and less PTPRC^low in children with obesity. Children with obesity had higher enrichment of the neutrophil degranulation, interleukin-7 (IL-7) receptor, and IL-7-related janus kinase-signal transducer and activator of transcription signaling pathways. Genes previously associated with more severe asthma, <i>IL-32</i>, <i>FKBP5</i> gene expression, <i>IL-6</i>, and Rho transcriptional signaling, were also enriched in obese children with asthma. Our findings shed insight into the molecular mechanisms underpinning more severe and steroid-resistant asthma among children with obesity. Further investigation is needed to identify potential new therapeutic targets for this group.<b>NEW & NOTEWORTHY</b> This study identified unique contributors to asthma in children with obesity and found novel pathways. Increased expression of IL-7R, IL-32, PARP-1, <i>FKBP5</i> gene, IL-6, and Rho transcriptional signaling were observed in obese individuals with asthma.