title: CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA.
abstract: Defining the molecular interactions required to program activated CD8 T cells to survive and become memory cells may allow us to understand how to augment anti-viral immunity. HVEM (herpes virus entry mediator) is a member of the tumor necrosis factor receptor (TNFR) family that interacts with ligands in the TNF family, LIGHT and Lymphotoxin-α, and in the Ig family, B and T lymphocyte attenuator (BTLA) and CD160. The Ig family members initiate inhibitory signaling when engaged with HVEM, but may also activate survival gene expression. Using a model of vaccinia virus infection, we made the unexpected finding that deficiency in HVEM or BTLA profoundly impaired effector CD8 T cell survival and development of protective immune memory. Mixed adoptive transfer experiments indicated that BTLA expressed in CD8α+ dendritic cells functions as a trans-activating ligand that delivers positive co-signals through HVEM expressed in T cells. Our data demonstrate a critical role of HVEM-BTLA bidirectional cosignaling system in antiviral defenses by driving the differentiation of memory CD8 T cells.
authors.affiliation: Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America ; La Jolla Institute for Allergy and Immunology, Divisions of Immune Regulation, San Diego, California, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Flynn
authors.forename: Tarun
authors.initials: T
authors.lastname: Hutchinson
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Shahram
authors.initials: S
authors.lastname: Salek-Ardakani
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011971:Receptors, Immunologic / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism*; D015398:Signal Transduction; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: C488868:BTLA protein, mouse; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14