Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells

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.