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A TNF Family Member LIGHT Transduces Costimulatory Signals into Human T Cells¹

Xiaochun Wan^2,*, Jun Zhang^2,, Hongyu Luo^*, Guixiu Shi^*, Elena Kapnik, Sunghee Kim, Palanisamy Kanakaraj and Jiangping Wu^3,*,

^* Laboratory of Transplantation Immunology and Nephrology Service of Notre Dame Hospital, Center Hospitalier de l’Universite de Montreal, University of Montreal, Montreal, Canada; and Human Genome Sciences, Rockville, MD

DcR3/TR6 is a secreted protein belonging to the TNFR family. It binds to Fas ligand, LIGHT, and TL1A, all of which are TNF family members. LIGHT is expressed on activated T cells. Its known receptors are TR2 and LTR on the cell surface, and TR6 in solution. In the present study, we report soluble TR6-Fc or solid-phase TR6-Fc costimulated proliferation, lymphokine production, and cytotoxicity of human T cells in the presence of TCR ligation. These costimulating effects were blocked by soluble LIGHT but not by soluble Fas-Fc. TR6-Fc could also effectively costimulate gld/gld mouse T cells. We further demonstrated that TR6 bound to both Th1 and Th2 cells, according to flow cytometry, and that the association was inhibited by soluble LIGHT. Cross-linking Th1 and Th2 cells with solid-phase TR6-Fc along with a suboptimal concentration of anti-CD3 enhanced proliferation of both Th1 and Th2 cells, and augmented Th1 but not Th2 lymphokine production. These data suggest that TR6 delivers costimulation through its ligand(s) on the T cell surface, and at least the major part of such costimulation is via LIGHT.

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