Mechanisms of Inhibition of Human Allergic Th2 Immune Responses by Regulatory T-Cells Induced by Interleukln 10-Treated Dendritic Cells and Transforming Growth Factor beta

摘要

Background: In grass pollen allergic individuals T-cell anergy can be induced by IL-10-treated dendritic cells (IL-10-DC) resulting in a decreased proliferation and Th1 as well as Th2 cyto-kine production. This study was set out to analyze whether such anergic T-cells are able to suppress the function of other T-cells and to analyze the role of TGF-beta as potential inducer of regulatory T-cells (Treg) in the periphery in this system. Methods: Freshly isolated CD4~+ or CD4~+ CD25- T-cells from grass pollen allergic donors were stimulated with autologous mature monocyte-derived allergen-pulsed dendritic cells in the presence or absence of T-cells previously cultured with IL-10-DC- and/or TGF-beta. Results: Anergic T-cells induced by allergen-pulsed IL- 10-treated DC or allergen-pulsed DC and TGF-P alone enhanced IL-10 production and strongly inhibited IFN-gamma production of fresh peripheral CD4~+ or CD4~+ CD25~- T-cells while proliferation and Th2 cytokine production were only slightly reduced. The addition of TGF-beta or the use of allergen-pulsed IL-10-treated DC and TGF-P had an additional effect leading to a much stronger suppression of Th2 cytokine production and proliferation. Suppression was not antigen-specific and was mainly mediated by cell-to-cell contact and by the molecule programmed death-1 (PD-1) and only partially by CTLA-4, TGF-beta and IL-10. Conclusions: These data demonstrate that regulatory/suppressor T-cells that also suppress Th2 cytokine production are induced most efficiently by DC that had been pretreated with IL-10 and by TGF-beta. This might be exploited for future therapeutic strategies for allergic diseases.