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Dual effects of TRAIL in suppression of autoimmunity: the inhibition of Th1 cells and the promotion of regulatory T cells.

Abstract
TRAIL is known to play a pivotal role in the inhibition of autoimmune disease. We previously demonstrated that administration of dendritic cells engineered to express TRAIL and myelin-oligodendrocyte glycoprotein reduced the severity of experimental autoimmune encephalomyelitis and suggested that CD4(+)CD25(+) regulatory T cells (Tregs) were involved in mediating this preventive effect. In the current study, we investigated the effect of TRAIL on Tregs, as well as conventional T cells, using TRAIL-deficient mice. Upon induction of experimental autoimmune encephalomyelitis, TRAIL-deficient mice showed more severe clinical symptoms, a greater frequency of IFN-γ-producing CD4(+) T (Th1) cells, and a lower frequency of CD4(+)Foxp3(+) Tregs than did wild-type mice. In vitro, conventional T cells stimulated by bone marrow-derived dendritic cells (BM-DCs) from TRAIL-deficient mice showed a greater magnitude of proliferation than did those stimulated by BM-DCs from wild-type mice. In contrast, TRAIL expressed on the stimulator BM-DCs enhanced the proliferative response of CD4(+)CD25(+) Tregs in the culture. The functional TRAILR, mouse death receptor 5 (mDR5), was expressed in conventional T cells and Tregs upon stimulation. In contrast, the decoy receptor, mDc-TRAILR1, was slightly expressed only on CD4(+)CD25(+) Tregs. Therefore, the distinct effects of TRAIL may be due to differences in the mDc-TRAILR1 expression or the signaling pathways downstream of mouse death receptor 5 between the two T cell subsets. Our data suggest that TRAIL suppresses autoimmunity by two mechanisms: the inhibition of Th1 cells and the promotion of Tregs.
AuthorsTokunori Ikeda, Shinya Hirata, Satoshi Fukushima, Yusuke Matsunaga, Takaaki Ito, Makoto Uchino, Yasuharu Nishimura, Satoru Senju
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 9 Pg. 5259-67 (Nov 01 2010) ISSN: 1550-6606 [Electronic] United States
PMID20921531 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfrsf10b protein, mouse
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor Decoy Receptors
Topics
  • Animals
  • Autoimmunity (immunology)
  • Cell Proliferation
  • Cell Separation
  • Encephalomyelitis, Autoimmune, Experimental (immunology)
  • Flow Cytometry
  • Immunohistochemistry
  • Lymphocyte Activation (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (immunology)
  • Signal Transduction (immunology)
  • T-Lymphocyte Subsets (immunology)
  • T-Lymphocytes, Regulatory (cytology, immunology)
  • TNF-Related Apoptosis-Inducing Ligand (immunology)
  • Th1 Cells (cytology, immunology)
  • Tumor Necrosis Factor Decoy Receptors (immunology)

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