Kondo, Tomoyuki The University of Tokushima
Kurosawa, Mie The University of Tokushima
Oura, Ritsuko The University of Tokushima
Matsumoto, Kazuma The University of Tokushima
Tanaka, Eiji The University of Tokushima Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Arakaki, Rieko The University of Tokushima Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Kudo, Yasusei The University of Tokushima Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Hayashi, Yoshio The University of Tokushima Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Ishimaru, Naozumi The University of Tokushima Tokushima University Educator and Researcher Directory KAKEN Search Researchers
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)-kB 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.
Methods and Finding: 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.
Conclusion: 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.
Copyright: © 2012 Izawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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pone_7_12_e48798.pdf 1.33 MB