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-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.
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Yumiko
Y
Matsumura
Takashi
T
Kobayashi
Kenji
K
Ichiyama
Ryoko
R
Yoshida
Masayuki
M
Hashimoto
Tomohito
T
Takimoto
Kentaro
K
Tanaka
Takatoshi
T
Chinen
Takashi
T
Shichita
Tony
T
Wyss-Coray
Katsuaki
K
Sato
Akihiko
A
Yoshimura
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12