Mechanisms of allergy and clinical immunologySelective deregulation in chemokine signaling pathways of CD4+CD25hiCD127lo/− regulatory T cells in human allergic asthma

BackgroundCD4+CD25hiCD127lo/− regulatory T cells have been suggested to be critical regulators of inflammatory processes in allergic asthma. Recent studies reported a selective decrease in the frequency of regulatory T cells in the bronchoalveolar lavage fluid of allergic asthmatic (AA) subjects, prompting the possibility of defective recruitment of these cells to the airway in response to chemokines produced during asthmatic inflammation.ObjectivesThis study aimed to characterize the chemotactic profile of circulating regulatory T cells in AA subjects in response to chemokines abundantly produced in airway inflammation, such as CCL1, CCL17, and CCL22.MethodsThe study was performed in a cohort of 26 AA, 16 healthy control, and 16 non-AA subjects. We used chemotaxis assays to evaluate cell migration, flow cytometry to examine chemokine receptor expression, and phospho-ELISA to study consequent signaling pathways in regulatory T cells.ResultsRegulatory T cells, but not CD4+CD25−T cells, from AA subjects showed decreased chemotactic responses, specifically to CCL1, in comparison with their healthy control and non-AA counterparts. Decreased CCL1-mediated chemotaxis in AA regulatory T cells was associated with decreased phosphorylation of protein kinase B (AKT), a protein involved in chemokine intracellular signaling. Furthermore, the decreased chemotactic response to CCL1 in AA regulatory T cells significantly correlated with asthma severity and decreased pulmonary function in AA subjects.ConclusionsThese results provide the first evidence of dysfunction in the chemokine signaling pathway in AA regulatory T cells.