Dendritic cells conditioned by activin-A-induced regulatory T cells exhibit enhanced tolerogenic properties and protect against experimental asthma.

Publication date: Available online 1 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Maria Semitekolou, Ioannis Morianos, Aggelos Banos, Dimitris Konstantopoulos, Marina Adamou-Tzani, Tim Sparwasser, Georgina Xanthou
BackgroundPreviously, we have demonstrated that regulatory T (Treg) cells, induced by the cytokine activin-A, suppress Th2-mediated allergic responses and linked airway disease. Still, the effects of activin-A-induced Treg cells (act-A-iTreg cells) on the regulation of dendritic cell (DC)-driven allergic inflammation remain elusive.ObjectiveHere, we investigated whether act-A-iTreg cells can modulate DC responses and endow them with enhanced tolerogenic functions.MethodsUsing adoptive cell transfer studies in mouse models of allergic airway disease, we examined the effects of act-A-iTreg cells on DC phenotype, maturation status and Th2 cell priming potential. Genome-wide gene expression profiling characterized the transcriptional networks induced in tolerogenic DCs by act-A-iTreg cells. The ability of DCs conditioned by act-A-iTreg cells (act-A-iTreg-modified DCs) to protect against experimental asthma and the mechanisms involved were also explored.ResultsAct-A-iTreg-modified DCs exhibited a significantly impaired capacity to uptake allergen and stimulate naive and Th2 effector responses upon allergen stimulation in vivo, accompanied by markedly attenuated inflammatory cytokine release in response to LPS. Gene-profiling studies revealed that act-A-iTreg cells dampened crucial Th2-skewing transcriptional networks in DCs. Administration of act-A-iTreg-modified DCs ameliorated cardinal asthma manifestations, in preventive and therapeutic protocols, through the generation of strongly-suppressive Foxp3⁺ Treg cells. Finally, PD-1/PD-L1 signaling pathways were essential in potentiating the generation of DCs with tolerogenic properties by act-A-iTreg cells.ConclusionOur studies reveal that act-A-iTreg cells instruct the generation of a highly effective immunoregulatory circuit encompassing tolerogenic DCs and Foxp3⁺ Treg cells that could be targeted for the design of novel immunotherapies for allergic disorders.

Teaser

This study uncovers a novel biological function for act-A-iTreg cells in instructing the generation of DCs with enhanced tolerogenic properties that could be targeted for the re-establishment of tolerance and the amelioration of asthmatic disease.


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