Nature Immunology6, 90 - 98 (2004)
Published online: 28 November 2004; | doi:10.1038/ni1144
B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator
John R Sedy1, Maya Gavrieli1, Karen G Potter2, Michelle A Hurchla1, R Coleman Lindsley1, Kai Hildner1, Stefanie Scheu3, Klaus Pfeffer3, Carl F Ware2, Theresa L Murphy1
& Kenneth M Murphy1, 4
1
Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
2
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
3
Institute of Medical Microbiology, University of Düsseldorf, Düsseldorf, Germany.
4
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
B and T lymphocyte attenuator (BTLA) provides an inhibitory signal to B and T cells. Previously, indirect observations suggested that B7x was a ligand for BTLA. Here we show that BTLA does not bind B7x; instead, we identify herpesvirus entry mediator (HVEM) as the unique BTLA ligand. BTLA bound the most membrane-distal cysteine-rich domain of HVEM, distinct from regions where the ligands LIGHT and lymphotoxin- bound HVEM. HVEM induced BTLA tyrosine phosphorylation and association of the tyrosine phosphatase SHP-2 and repressed antigen-driven T cell proliferation, providing an example of reverse signaling to a non−tumor necrosis factor family ligand. The conservation of the BTLA-HVEM interaction between mouse and human suggests that this system is an important pathway regulating lymphocyte activation and/or homeostasis in the immune response.
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bound HVEM. HVEM induced BTLA tyrosine phosphorylation and association of the tyrosine phosphatase SHP-2 and repressed antigen-driven T cell proliferation, providing an example of reverse signaling to a non−tumor necrosis factor family ligand. The conservation of the BTLA-HVEM interaction between mouse and human suggests that this system is an important pathway regulating lymphocyte activation and/or homeostasis in the immune response.
