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

Background Previously, we demonstrated that regulatory T (Treg) cells induced by the cytokine activin-A suppress T H 2-mediated allergic responses and linked airway disease. Still, the effects of activin-A–induced regulatory T (Act-A-iTreg) cells on the regulation of dendritic cell (DC)–driven allergic inflammation remain elusive. Objective Here we investigated whether Act-A-iTreg cells can modulate DC responses and endow them with enhanced tolerogenic functions. Methods Using 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 T H 2 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 cell–modified DCs) to protect against experimental asthma, and the mechanisms involved were also explored. Results Act-A-iTreg cell–modified DCs exhibited a significantly impaired capacity to uptake allergen and stimulate naive and T H 2 effector responses on 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 T H 2-skewing transcriptional networks in DCs. Administration of Act-A-iTreg cell–modified DCs ameliorated cardinal asthma manifestations in preventive and therapeutic protocols through generation of strongly suppressive forkhead box P3 + Treg cells. Finally, programed death protein 1/programmed death ligand 1 signaling pathways were essential in potentiating the generation of DCs with tolerogenic properties by Act-A-iTreg cells. Conclusion Our studies reveal that Act-A-iTreg cells instruct the generation of a highly effective immunoregulatory circuit encompassing tolerogenic DCs and forkhead box P3 + Treg cells that could be targeted for the design of novel immunotherapies for allergic disorders.