title: Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway.
abstract: B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor that interacts with herpesvirus entry mediator (HVEM), and this interaction regulates pathogenesis in various immunologic diseases. In graft-versus-host disease (GVHD), BTLA unexpectedly mediates positive effects on donor T-cell survival, whereas immunologic mechanisms of this function have yet to be explored. In this study, we elucidated a role of BTLA in GVHD by applying the newly established agonistic anti-BTLA monoclonal antibody that stimulates BTLA signal without antagonizing BTLA-HVEM interaction. Our results revealed that provision of BTLA signal inhibited donor antihost T-cell responses and ameliorated GVHD with a successful engraftment of donor hematopoietic cells. These effects were dependent on BTLA signal into donor T cells but neither donor non-T cells nor recipient cells. On the other hand, expression of BTLA mutant lacking an intracellular signaling domain restored impaired survival of BTLA-deficient T cells, suggesting that BTLA also serves as a ligand that delivers HVEM prosurvival signal in donor T cells. Collectively, current study elucidated dichotomous functions of BTLA in GVHD to serve as a costimulatory ligand of HVEM and to transmit inhibitory signal as a receptor.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Sakoda
authors.forename: Jang-June
authors.initials: JJ
authors.lastname: Park
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kuramasu
authors.forename: Degui
authors.initials: D
authors.lastname: Geng
authors.forename: Yingjia
authors.initials: Y
authors.lastname: Liu
authors.forename: Eduardo
authors.initials: E
authors.lastname: Davila
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002470:Cell Survival; D006086:Graft vs Host Disease / Q000276:immunology*; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C488868:BTLA protein, mouse; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse