Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5121-6. doi: 10.1073/pnas.1222093110. Epub 2013 Mar 11.
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.
尽管先天免疫反应对于启动获得性免疫反应以及随后成功清除病原体是必要的，但过度的反应偶尔会导致致命的内毒素休克，并伴有细胞因子风暴。B 和 T 淋巴细胞衰减器（BTLA）是一种与细胞毒性 T 淋巴细胞抗原（CTLA）-4 和程序性死亡（PD）-1 相似的共抑制受体，不仅在 B 和 T 细胞中表达，而且在树突状细胞（DC）和巨噬细胞（Mϕ）中表达。最近，几项研究报道，BTLA 缺陷（BTLA(-/-)）小鼠在感染早期比 WT 小鼠更能清除病原体。然而，先天细胞上表达的 BTLA 在过度和失控的免疫反应中的作用尚不清楚。在这里，我们发现 BTLA(-/-) 小鼠对内毒素诱导的内毒素休克高度敏感。BTLA(-/-) 小鼠中 LPS 诱导的 DC 和 Mϕ 产生的 TNF-α 和 IL-12 明显增强。BTLA(-/-) DC 在受到 Pam3CSK4 刺激时也产生高水平的 TNF-α，但不受 poly(I:C)或 CpG 刺激，表明 BTLA 作为细胞表面 Toll 样受体信号的抑制分子起作用，但不是内体。此外，BTLA(-/-) DC 在 LPS 刺激下显示出增强的 MyD88 和 toll/IL-1R 域包含衔接诱导 IFN（TRIF）依赖性信号，这与脂质筏中 Src 同源 2 包含蛋白酪氨酸磷酸酶的积累受损有关。最后，我们发现，一种激动性抗 BTLA 抗体可以使 LPS 诱导的内毒素休克小鼠获救，即使在已经出现内毒素休克迹象的小鼠中给予该抗体。这些结果表明，BTLA 直接抑制 DC 和 Mϕ 中的 LPS 反应，BTLA 的激动剂可能对内毒素诱导的内毒素休克具有治疗潜力。
