Islet antigen-pulsed dendritic cells expressing ectopic IL-35Ig protect nonobese diabetic mice from autoimmune diabetes.

Dendritic cells (DCs) are professional antigen presenting cells capable of orchestrating either stimulatory or regulatory immune responses mediated by T cells. Interleukin 35 (IL-35) is an immunosuppressive, heterodimeric cytokine belonging to the IL-12 family and known to be produced by regulatory T cells but not DCs. In this study, we explored the possible immunosuppressive effect of IL-35 ectopically expressed by splenic DCs from nonobese diabetic (NOD) mice, a prototypical model of autoimmune diabetes. After pulsing with the IGRP peptide (a dominant, diabetogenic autoantigen in NOD mice) and transfer in vivo, IL-35Ig- but not Ig-transfected DCs suppressed antigen specific, T cell-mediated responses in a skin test assay. More importantly, transfer of IL-35Ig-transfected, IGRP-pulsed DCs into prediabetic NOD mice induced a delayed and less severe form of diabetes, an effect accompanied by the increase of CD4(+)CD39(+) suppressive T cells in pancreatic lymph nodes. Our data therefore suggest that DCs overexpressing ectopic IL-35Ig might represent a powerful tool in negative vaccination strategies.