Enhanced production of CCL18 by tolerogenic dendritic cells is associated with inhibition of allergic airway reactivity.

Abstract

IL-10-treated dendritic cells (DCs) have been shown to inhibit T-cell responses through induction of anergy and regulatory T cells in various model systems, including allergic inflammation, but the factors being involved in this inhibition are still unclear. This study set out to analyze such factors produced or induced by IL-10-treated DCs by using gene expression profiling and to explore their function. CD4(+) T cells from allergic donors were stimulated with autologous monocyte-derived allergen-pulsed mature DCs or IL-10-treated DCs. After 24 hours, the transcriptional profile was analyzed by using Affymetrix technology. Results were validated by using quantitative real-time PCR, protein expression, and functional in vitro and in vivo studies. In CD4(+) T-cell/IL-10-treated DC cocultures the expression of several known genes, such as IL13, IL5 and OX40, was suppressed. Interestingly, there was only one factor that was strongly upregulated: the DC-derived chemokine CCL18. In vitro addition of CCL18 to cocultures of CD4(+) T cells and allergen-pulsed DCs resulted in a similar inhibition of T(H)2 cytokine production as induced by allergen-pulsed IL-10-treated DCs without exogenous CCL18, whereas T(H)1 cytokine production, IL-10 production, and proliferation were not affected. Furthermore, in a humanized mouse model of allergy using PBMC-engrafted NOD-scid-γc(-/-) mice, CCL18, but not another T(H)2-associated chemokine, CCL17, inhibited airway reactivity and lung inflammation. Chemotaxis assays revealed that CCL18 preferentially attracted regulatory T cells and, less efficiently, T(H)2 cells. These data demonstrate that CCL18 might represent a molecule of significant importance in immunoregulation and might be a therapeutic target in patients with allergic airway diseases.