B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator.
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-alpha 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.
Sedy
John R
JR
Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Gavrieli
Maya
M
Potter
Karen G
KG
Hurchla
Michelle A
MA
Lindsley
R Coleman
RC
Hildner
Kai
K
Scheu
Stefanie
S
Pfeffer
Klaus
K
Ware
Carl F
CF
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
D000818:Animals; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000378:metabolism* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology
C488868:BTLA protein, mouse; D008024:Ligands; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C506028:TNFRSF14 protein, human; C506029:Tnfrsf14 protein, mouse