Cheung, Timothy C.;
Oborne, Lisa M.;
Steinberg, Marcos W.;
Macauley, Matthew G.;
Fukuyama, Satoshi;
Sanjo, Hideki;
D'Souza, Claire;
Norris, Paula S.;
Pfeffer, Klaus;
Murphy, Kenneth M.;
Kronenberg, Mitchell;
Spear, Patricia G.;
Ware, Carl F.
T Cell Intrinsic Heterodimeric Complexes between HVEM and BTLA Determine Receptivity to the Surrounding Microenvironment
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Medientyp:
E-Artikel
Titel:
T Cell Intrinsic Heterodimeric Complexes between HVEM and BTLA Determine Receptivity to the Surrounding Microenvironment
Beteiligte:
Cheung, Timothy C.;
Oborne, Lisa M.;
Steinberg, Marcos W.;
Macauley, Matthew G.;
Fukuyama, Satoshi;
Sanjo, Hideki;
D'Souza, Claire;
Norris, Paula S.;
Pfeffer, Klaus;
Murphy, Kenneth M.;
Kronenberg, Mitchell;
Spear, Patricia G.;
Ware, Carl F.
Erschienen:
The American Association of Immunologists, 2009
Erschienen in:The Journal of Immunology
Sprache:
Englisch
DOI:
10.4049/jimmunol.0902490
ISSN:
0022-1767;
1550-6606
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-κB RelA transcriptional complex raising the question of how NF-κB activation is repressed in naive T cells. In this study, we show BTLA interacts with HVEM in cis, forming a heterodimeric complex in naive T cells that inhibits HVEM-dependent NF-κB activation. The cis-interaction between HVEM and BTLA is the predominant form expressed on the surface of naive human and mouse T cells. The BTLA ectodomain acts as a competitive inhibitor blocking BTLA and CD160 from binding in trans to HVEM and initiating NF-κB activation. The TNF-related ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14) binds HVEM in the cis-complex, but NF-κB activation was attenuated, suggesting BTLA prevents oligomerization of HVEM in the cis-complex. Genetic deletion of BTLA or pharmacologic disruption of the HVEM-BTLA cis-complex in T cells promoted HVEM activation in trans. Interestingly, herpes simplex virus envelope glycoprotein D formed a cis-complex with HVEM, yet surprisingly, promoted the activation NF-κB RelA. We suggest that the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state.</jats:p>