Sun Yonglian, Brown Nicholas K, Ruddy Matthew J, Miller Mendy L, Lee Youjin, Wang Yang, Murphy Kenneth M, Pfeffer Klaus, Chen Lieping, Kaye Jonathan, Fu Yang-Xin
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
J Immunol. 2009 Aug 1;183(3):1946-51. doi: 10.4049/jimmunol.0801866. Epub 2009 Jul 8.
Coinhibitory pathways are thought to act in later stages of an adaptive immune response, but whether coinhibition contributes to early innate immunity is unclear. We show that engagement of the newly discovered coinhibitory receptor B and T lymphocyte attenuator (BTLA) by herpesvirus entry mediator (HVEM) is critical for negatively regulating early host immunity against intracellular bacteria. Both HVEM(-/-) and BTLA(-/-), but not LIGHT(-/-), mice are more resistant to listeriosis compared with wild-type mice, and blockade of the BTLA pathway promotes, while engagement inhibits, early bacterial clearance. Differences in bacterial clearance were seen as early as 1 day postinfection, implicating the initial innate response. Therefore, innate cell function in BTLA(-/-) mice was studied. We show that innate cells from BTLA(-/-) mice secrete significantly more proinflammatory cytokines upon stimulation with heat-killed Listeria. These results provide the first evidence that a coinhibitory pathway plays a critical role in regulating early host innate immunity against infection.
共抑制通路被认为在适应性免疫反应的后期起作用，但共抑制是否有助于早期固有免疫尚不清楚。我们发现，疱疹病毒侵入介质（HVEM）与新发现的共抑制受体B和T淋巴细胞衰减器（BTLA）的结合对于负向调节宿主针对细胞内细菌的早期免疫至关重要。与野生型小鼠相比，HVEM（-/-）和BTLA（-/-）小鼠（而非LIGHT（-/-）小鼠）对李斯特菌病更具抵抗力，阻断BTLA通路可促进早期细菌清除，而激活该通路则会抑制早期细菌清除。早在感染后1天就观察到细菌清除的差异，这表明初始固有免疫反应发挥了作用。因此，我们研究了BTLA（-/-）小鼠的固有细胞功能。我们发现，用热灭活的李斯特菌刺激后，BTLA（-/-）小鼠的固有细胞分泌的促炎细胞因子明显更多。这些结果首次证明，共抑制通路在调节宿主针对感染的早期固有免疫中起关键作用。
