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* Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan;
Laboratory for Dendritic Cell Immunobiology, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Tsurumi-ku, Yokohama, Japan; and
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305
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-
Ab, and SOCS3–/– DCs produced higher levels of TGF- than WT-DCs, suggesting that TGF- 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.
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1 This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports and Culture of Japan (to A.Y. and K.T.), the Yamanouchi Foundation for Research on Metabolic Disorders (to A.Y.), the Takeda Science Foundation (to K.T.), the Kato Memorial Foundation (to K.T.), the Kanae Foundation for the Promotion of Medical Science (to K.T.), and the Uehara Memorial Foundation (to T.C.).
2 Address correspondence and reprint requests to Dr. Akihiko Yoshimura, Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: yakihiko{at}bioreg.kyushu-u.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; EAE, experimental autoimmune encephalomyelitis; KLH, keyhole limpet hemocyanin; LN, lymph node; LysM, lysozyme M; MOG, myelin oligodendrocyte glycoprotein; SEAP, secreted alkaline phosphatase; SOCS, suppressor of cytokine signaling; Tr1, IL-10-producing regulatory T; Treg, T regulatory; WT, wild type.
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