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

Abstract

Background: Previously, we 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 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 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 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 TH2 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 TH2-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.