title: Regulation of antigen-expressing dendritic cells by double negative regulatory T cells.
abstract: TCRαβ(+) CD3(+) CD4(-) CD8(-) NK1.1(-)  double negative (DN) Tregs comprise 1-3% of peripheral T lymphocytes in mice and humans. It has been demonstrated that DN Tregs can suppress allo-, xeno- and auto-immune responses in an Ag-specific fashion. However, the mechanisms by which DN Tregs regulate immune responses remain elusive. Whether DN Tregs can regulate DCs has not been investigated previously. In this study, we demonstrate that DN Tregs express a high level of CTLA4 and are able to down-regulate costimulatory molecules CD80 and CD86 expressed on Ag-expressing mature DCs (mDCs). DN Tregs from CTLA4 KO mice were not able to downregulate CD80 and CD86 expression, indicating that CTLA4 is critical for DN Treg-mediated downregulation of costimulatory molecule expression on Ag-expressing mature DCs. Furthermore, DN Tregs could kill both immature and mature allogeneic DCs, as well as Ag-loaded syngeneic DCs, in an Ag-specific manner in vitro and in vivo, mainly through the Fas-FasL pathway. These data demonstrate, for the first time, that DN Tregs are potent regulators of DCs and may have the potential to be developed as a novel immune suppression treatment.
authors.affiliation: University of Toronto Transplant Institute, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Julia Fang
authors.initials: JF
authors.lastname: Gao
authors.forename: Megan S Ford
authors.initials: MS
authors.lastname: McIntyre
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Juvet
authors.forename: Jun
authors.initials: J
authors.lastname: Diao
authors.forename: Xujian
authors.initials: X
authors.lastname: Li
authors.forename: Ramesh B
authors.initials: RB
authors.lastname: Vanama
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cattral
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse