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-beta Ab, and SOCS3(-/-) DCs produced higher levels of TGF-beta than WT-DCs, suggesting that TGF-beta 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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B7-2 Antigen / genetics
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B7-2 Antigen / immunology
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CD40 Antigens / genetics
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CD40 Antigens / immunology
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Cell Proliferation*
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Coculture Techniques
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Dendritic Cells / immunology*
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology*
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology
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Immune Tolerance / drug effects
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Immune Tolerance / genetics
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Immune Tolerance / immunology*
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Mice
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Mice, Knockout
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / deficiency
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Suppressor of Cytokine Signaling Proteins / immunology*
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T-Lymphocytes, Regulatory / immunology*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology
Substances
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Antibodies
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B7-2 Antigen
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CD40 Antigens
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Cd86 protein, mouse
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Histocompatibility Antigens Class II
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Transforming Growth Factor beta
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Interleukin-10
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Interleukin-12