Ambient air pollution impairs regulatory T-cell function in asthma

Abstract

Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response. To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores. Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n= 71, and Fresno Non Asthmatic Group, n= 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n= 40, and Stanford Non Asthmatic Group, n= 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score. Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P≤ .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P≤ .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P≤ .05). Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.