title: Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice.
abstract: Foxp3(+) regulatory T cells (T reg cells) effectively suppress immunity, but it is not determined if antigen-induced T reg cells (iT reg cells) are able to persist under conditions of inflammation and to stably express the transcription factor Foxp3. We used spleen cells to stimulate the mixed leukocyte reaction (MLR) in the presence of transforming growth factor β (TGF-β) and retinoic acid. We found that the CD11c(high) dendritic cell fraction was the most potent at inducing high numbers of alloreactive Foxp3(+) cells. The induced CD4(+)CD25(+)Foxp3(+) cells appeared after extensive proliferation. When purified from the MLR, iT reg cells suppressed both primary and secondary MLR in vitro in an antigen-specific manner. After transfer into allogeneic mice, iT reg cells persisted for 6 mo and prevented graft versus host disease (GVHD) caused by co-transferred CD45RB(hi) T cells. Similar findings were made when iT reg cells were transferred after onset of GVHD. The CNS2 intronic sequence of the Foxp3 gene in the persisting iT reg cells was as demethylated as the corresponding sequence of naturally occurring T reg cells. These results indicate that induced Foxp3(+) T reg cells, after proliferating and differentiating into antigen-specific suppressive T cells, can persist for long periods while suppressing a powerful inflammatory disease.
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Disease, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Sela
authors.forename: Peter
authors.initials: P
authors.lastname: Olds
authors.forename: Andrew
authors.initials: A
authors.lastname: Park
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Schlesinger
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000818:Animals; D039521:CD11c Antigen; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D039521:CD11c Antigen; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
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