B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells.

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作者：

Y Kobayashi，A Iwata，K Suzuki，A Suto，S Kawashima，Y Saito，T Owada，M Kobayashi，N Watanabe，H Nakajima

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摘要：

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 (M phi s). 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-alpha and IL-12 production in DCs and M phi s was significantly enhanced in BTLA(-/-) mice. BTLA(-/-) DCs also produced high levels of TNF-alpha 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 M phi s and that agonistic agents for BTLA might have therapeutic potential for LPS-induced endotoxic shock.

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关键词：

SEPTIC SHOCK I INTERFERON SEPSIS BTLA ACTIVATION PATHOGENESIS RECOGNITION DYSFUNCTION MORTALITY RESPONSES