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-α 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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We thank D. Fremont, C. Nelson and O. Naidenko for help with tetramer production and for discussions, and V. Grigura and J.C. Walsh for technical assistance. Supported by the Howard Hughes Medical Institute (K.M.M.) and the National Institutes of Health (PO1 AI31238 and P50 HL54619 to K.M.M.; AI33068, CA69381 and AI48073 to C.F.W.; and AG00252 to K.P.).
Some of the authors have applied for a patent that concerns the BTLA-HVEM interaction and its uses.
BTLA does not directly interact with B7x. (PDF 39 kb)
Sequences of HVEM isolated from retroviral library. (PDF 45 kb)
Expression of BTLA and HVEM by EL-4 cells. (PDF 26 kb)
Increased expression of HVEM by Btla−/− lymphocytes. (PDF 49 kb)
Expression of I-Ad, B7.1, BTLA and HVEM on CHO cells. (PDF 56 kb)
Oligonucleotide sequences used in plasmid construction. (PDF 11 kb)
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Sedy, J., Gavrieli, M., Potter, K. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6, 90–98 (2005). https://doi.org/10.1038/ni1144
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