CD4+CD25+ regulatory T cells suppress Th17-responses in an experimental colitis model.
BACKGROUND
After the recent discovery of Th17 cells, it was proposed that Th17 responses are involved in the pathogenesis of inflammatory bowel diseases (IBD). CD4(+)CD25(+) regulatory T cells (Treg) are considered to be an attractive tool for the treatment of IBD. Here, we investigated whether Treg are capable of suppressing Th17-mediated colitis.


METHODS
Naive CD4(+) T cells were transferred into SCID mice with or without Treg. In some experiments, Treg were transferred into recipient mice with established colitis. Mice treated with Treg were injected with an anti-transforming growth factor (TGF)-β mAb or control IgG. Clinical symptoms of colitis, histological changes and cytokine expressions were investigated.


RESULTS
SCID mice transferred with naive CD4(+) T cells developed chronic colitis with significant increases in Th1 and Th17 cytokine expressions in the colon. When Treg were co-transferred with naive CD4(+) T cells, development of colitis was prevented, and Th17 cytokine expressions were markedly reduced. Similarly, when Treg were transferred into mice with established colitis, the colitis was significantly ameliorated in association with dramatic reductions in Th17 cytokine expressions. Injection of anti-TGF-β mAb abolished the Treg-mediated suppression with significant elevations in Th17 cytokine productions.


CONCLUSIONS
This adoptive transfer model of colitis was associated with augmented Th1 and Th17 responses, and Treg were capable of suppressing colonic inflammation by downregulating Th17 responses as well as Th1 responses via TGF-β. Consequently, Treg transfer therapy is expected to be efficacious for IBD even if Th17 is involved in the pathogenesis.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Haruei
H
Ogino
Kazuhiko
K
Nakamura
Eikich
E
Ihara
Hirotada
H
Akiho
Ryoichi
R
Takayanagi
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology*; D005786:Gene Expression Regulation / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000502:physiology; D058504:Th17 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta