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Impaired IL-10–dependent Induction of Tolerogenic Dendritic Cells by CD4⁺CD25^hiCD127^lo/– Natural Regulatory T Cells in Human Allergic Asthma

¹ Department of Pediatrics, Stanford University, Stanford, California

Correspondence and requests for reprints should be addressed to Kari C. Nadeau, M.D., Ph.D., Pulmonary Center of Excellence, Stanford University, Stanford, CA 94305. E-mail: knadeau{at}stanford.edu

Rationale: Tolerogenic dendritic cells and natural regulatory T cells have been implicated in the process of infectious tolerance in human allergic asthma. However, the significance of the influence of natural regulatory T cells on tolerogenic dendritic cells in the disease has not been investigated.

Objectives: We aimed to characterize the mechanism of induction of the tolerogenic phenotype in circulating blood dendritic cells by allergic asthmatic natural regulatory T cells.

Methods: The study was performed in a cohort of 21 subjects with allergic asthma, 21 healthy control subjects, and 21 subjects with nonallergic asthma. We cultured blood dendritic cells with natural regulatory T cells to study the induction of tolerogenic dendritic cells. Flow cytometry and proliferation assays were employed to analyze phenotype and function of dendritic cells as well as IL-10 production from natural regulatory T cells.

Measurements and Main Results: Dendritic cells cultured with natural regulatory T cells up-regulated IL-10, down-regulated costimulatory molecules, and stimulated the proliferation of CD4⁺CD25^– effector T cells less potently. Allergic asthmatic natural regulatory T cells were significantly less efficient in inducing this tolerogenic phenotype of dendritic cells compared with healthy control and nonallergic asthmatic counterparts. Furthermore, this defective function of natural regulatory T cells was associated with their decreased IL-10 expression, disease severity, and could be reversed by oral corticosteroid therapy.

Conclusions: These results provided the first evidences of impaired induction of tolerogenic dendritic cells mediated by natural regulatory T cells in human allergic asthma.

Key Words: asthma • natural regulatory T cells • dendritic cells • IL-10 • infectious tolerance

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Evidence suggests that tolerogenic dendritic cells can augment beneficial natural regulatory T-cell function in allergic asthma, but the existence of a converse mechanism by which natural regulatory T cells mediate the induction of tolerogenic dendritic cells has not been explored. What This Study Adds to the Field Induction of tolerogenic dendritic cells by human allergic asthmatic natural regulatory T cells is impaired, due in part to reduced IL-10 expression, a defect that can be ameliorated by oral corticosteroids.