造血谱系细胞中的Toll样受体4信号传导有助于增强人类疫苗佐剂AS01的活性。,European Journal of Immunology

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造血谱系细胞中的Toll样受体4信号传导有助于增强人类疫苗佐剂AS01的活性。
European Journal of Immunology ( IF 4.5 ) Pub Date : 2019-09-26 , DOI: 10.1002/eji.201948234
Laurye Van Maele ₁ , Delphine Fougeron ₁ , Delphine Cayet ₁ , Aurélie Chalon ₂ , Diego Piccioli ₂ , Catherine Collignon ₂ , Jean-Claude Sirard ₁ , Arnaud M Didierlaurent ₂

Affiliation

3-O-去酰基-4'-单磷酰基脂质A（MPL）通过Toll样受体4（TLR4）信号传导激活免疫力。辅助系统AS01包含MPL，用于候选疟疾疫苗和许可的带状疱疹疫苗。最近的研究报道，AS01佐剂的活性取决于疫苗接种部位的短暂炎症，但基质细胞或结构细胞在佐剂作用中的作用尚不清楚。我们通过评估TLR4在AS01佐剂疫苗免疫过程中对造血细胞和驻留结构细胞的作用，在小鼠模型中调查了这个问题。我们首先确定缺乏TLR4的动物对AS01佐剂疫苗的免疫反应降低。使用骨髓嵌合体，我们始终发现Tlr4在放射敏感性细胞（即造血细胞）中表达，对于抗体和T细胞反应的最佳佐剂作用是必需的。注射后第1天，注射部位的促炎反应强烈依赖于造血细胞中的TLR4信号传导。类似地，排水肌肉的淋巴结中树突状细胞的激活与表达Tlr4的放射敏感性细胞严格相关。总之，这些数据表明，造血细胞中MPL介导的TLR4信号在AS01的作用方式中至关重要。

"点击查看英文标题和摘要"

Toll-like receptor 4 signaling in hematopoietic-lineage cells contributes to the enhanced activity of the human vaccine adjuvant AS01.

The 3-O-desacyl-4'-monophosphoryl lipid A (MPL) activates immunity through Toll-like receptor 4 (TLR4) signaling. The Adjuvant System AS01 contains MPL and is used in the candidate malaria vaccine and the licensed zoster vaccine. Recent studies reported that AS01 adjuvant activity depends on a transient inflammation at the site of vaccination, but the role of stromal or structural cells in the adjuvant effect is unknown. We investigated this question in mouse models by assessing the role of TLR4 on hematopoietic versus resident structural cells during immunization with AS01-adjuvanted vaccines. We first established that TLR4-deficient animals had a reduced immune response to an AS01-adjuvanted vaccine. Using bone marrow chimera, we consistently found that Tlr4 expression in radio-sensitive cells, i.e., hematopoietic cells, was required for an optimal adjuvant effect on antibody and T-cell responses. At day 1 after injection, the pro-inflammatory reaction at the site of injection was strongly dependent on TLR4 signaling in hematopoietic cells. Similarly, activation of dendritic cells in muscle-draining lymph nodes was strictly associated with the radio-sensitive cells expressing Tlr4. Altogether, these data suggest that MPL-mediated TLR4-signaling in hematopoietic cells is critical in the mode of action of AS01.

更新日期：2019-09-26

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