title: CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells.
abstract: Lymphocyte activation is regulated by costimulatory and inhibitory receptors, of which both B and T lymphocyte attenuator (BTLA) and CD160 engage herpesvirus entry mediator (HVEM). Notably, it remains unclear how HVEM functions with each of its ligands during immune responses. In this study, we show that HVEM specifically activates CD160 on effector NK cells challenged with virus-infected cells. Human CD56(dim) NK cells were costimulated specifically by HVEM but not by other receptors that share the HVEM ligands LIGHT, Lymphotoxin-α, or BTLA. HVEM enhanced human NK cell activation by type I IFN and IL-2, resulting in increased IFN-γ and TNF-α secretion, and tumor cell-expressed HVEM activated CD160 in a human NK cell line, causing rapid hyperphosphorylation of serine kinases ERK1/2 and AKT and enhanced cytolysis of target cells. In contrast, HVEM activation of BTLA reduced cytolysis of target cells. Together, our results demonstrate that HVEM functions as a regulator of immune function that activates NK cells via CD160 and limits lymphocyte-induced inflammation via association with BTLA.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford|Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Šedý
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Bjordahl
authors.forename: Vasileios
authors.initials: V
authors.lastname: Bekiaris
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Macauley
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ware
authors.forename: Paula S
authors.initials: PS
authors.lastname: Norris
authors.forename: Nell S
authors.initials: NS
authors.lastname: Lurain
authors.forename: Chris A
authors.initials: CA
authors.lastname: Benedict
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D019002:CD56 Antigen / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D058851:GPI-Linked Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C482586:BTLA protein, human; C114505:CD160 protein, human; D019002:CD56 Antigen; D058851:GPI-Linked Proteins; D007370:Interferon Type I; D007376:Interleukin-2; D008233:Lymphotoxin-alpha; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3