Selective Expansion of Foxp3-Positive Regulatory T Cells and Immunosuppression by Suppressors of Cytokine Signaling 3-Deficient Dendritic Cells

Abstract

Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10+ Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4+ T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3+ Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3+ T cell-inducing tolerogenic DCs. SOCS3−/− DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3− effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3+ Treg cells were selectively expanded by SOCS3−/− DCs. Adoptive transfer of SOCS3−/− DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3+ T cell expansion was blocked by anti-TGF-β Ab, and SOCS3−/− DCs produced higher levels of TGF-β than WT-DCs, suggesting that TGF-β plays an essential role in the expansion of Foxp3+ Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.