title: B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells.
abstract: Although innate immune responses are necessary for the initiation of acquired immune responses and the subsequent successful elimination of pathogens, excessive responses occasionally result in lethal endotoxic shock accompanied by a cytokine storm. B and T lymphocyte attenuator (BTLA), a coinhibitory receptor with similarities to cytotoxic T-lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, is expressed in not only B and T cells but also dendritic cells (DCs) and macrophages (Mϕs). Recently, several studies have reported that BTLA-deficient (BTLA(-/-)) mice show enhanced pathogen clearance compared with WT mice in early phase of infections. However, the roles of BTLA expressed on innate cells in overwhelming and uncontrolled immune responses remain unclear. Here, we found that BTLA(-/-) mice were highly susceptible to LPS-induced endotoxic shock. LPS-induced TNF-α and IL-12 production in DCs and Mϕs was significantly enhanced in BTLA(-/-) mice. BTLA(-/-) DCs also produced high levels of TNF-α on stimulation with Pam3CSK4 but not poly(I:C) or CpG, suggesting that BTLA functions as an inhibitory molecule on Toll-like receptor signaling at cell surface but not endosome. Moreover, BTLA(-/-) DCs showed enhanced MyD88- and toll/IL-1R domain-containing adaptor inducing IFN (TRIF)-dependent signaling on LPS stimulation, which is associated with impaired accumulation of Src homology 2-containing protein tyrosine phosphatase in lipid rafts. Finally, we found that an agonistic anti-BTLA antibody rescued mice from LPS-induced endotoxic shock, even if the antibody was given to mice that had developed a sign of endotoxic shock. These results suggest that BTLA directly inhibits LPS responses in DCs and Mϕs and that agonistic agents for BTLA might have therapeutic potential for LPS-induced endotoxic shock.
authors.affiliation: Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Arifumi
authors.initials: A
authors.lastname: Iwata
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Suto
authors.forename: Saki
authors.initials: S
authors.lastname: Kawashima
authors.forename: Yukari
authors.initials: Y
authors.lastname: Saito
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Owada
authors.forename: Midori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D011992:Endosomes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D007369:Interferon Inducers / Q000494:pharmacology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D007369:Interferon Inducers; D018664:Interleukin-12; D055666:Lipopeptides; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011070:Poly I-C; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C488868:BTLA protein, mouse; C507780:Myd88 protein, mouse; C508075:Pam(3)CSK(4) peptide; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse