title: Fas-independent T-cell apoptosis by dendritic cells controls autoimmune arthritis in MRL/lpr mice.
abstract: BACKGROUND
  Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity.
  
  
  RESULTS
  Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4(+) T, B, and CD4(-)CD8(-) double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice.
  
  
  CONCLUSIONS
  These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice.
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kondo
authors.forename: Mie
authors.initials: M
authors.lastname: Kurosawa
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Oura
authors.forename: Kazuma
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamada
authors.forename: Rieko
authors.initials: R
authors.lastname: Arakaki
authors.forename: Yasusei
authors.initials: Y
authors.lastname: Kudo
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D051379:Mice; D019463:Mice, Inbred MRL lpr; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor
chemical_list: D053245:RANK Ligand; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D019014:fas Receptor