TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells
TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells
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DOI：
10.1016/j.intimp.2023.109852
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发表时间：
2023-02-18
影响因子：
5.6
通讯作者：
Kunisawa，Jun
中科院分区：
文献类型：
--
作者：
Sun，Xiao;Hosomi，Koji;Kunisawa，Jun
粪产碱杆菌先前被鉴定为肠淋巴组织驻留的肠道细菌，我们随后的研究表明脂多糖及其核心活性成分（即，脂质A）具有有效佐剂活性以优先促进抗原特异性Th 17应答和抗体产生。在这里，我们比较A。粪脂A（ALA）与单磷酰脂质A，一种许可的基于脂质A的佐剂，阐明ALA佐剂特性的免疫学机制。与单磷酰脂质A相比，ALA诱导更高水平的MHC II类分子和树突状细胞（DC）上的共刺激分子CD 40、CD 80和CD 86，这反过来又导致强烈的T细胞活化。此外，ALA比单磷酰脂质A更有效地促进DC产生IL-6和IL-23，从而导致优先诱导Th 17和Th 1细胞。作为潜在机制，我们发现ALA-TLR 4轴刺激MyD 88和TRIF介导的信号通路，而单磷酰脂质A偏向TRIF信号通路。这些发现揭示了ALA对DC和T细胞的作用及其对信号通路的诱导模式。
Alcaligenes faecaliswas previously identified as an intestinal lymphoid tissue-resident commensal bacteria, and our subsequent studies showed that lipopolysaccharide and its core active element (i.e., lipid A) have a potent adjuvant activity to promote preferentially antigen-specific Th17 response and antibody production. Here, we comparedA. faecalislipid A (ALA) with monophosphoryl lipid A, a licensed lipid A–based adjuvant, to elucidate the immunological mechanism underlying the adjuvant properties of ALA. Compared with monophosphoryl lipid A, ALA induced higher levels of MHC class II molecules and costimulatory CD40, CD80, and CD86 on dendritic cells (DCs), which in turn resulted in strong T cell activation. Moreover, ALA more effectively promoted the production of IL-6 and IL-23 from DCs than did monophosphoryl lipid A, thus leading to preferential induction of Th17 and Th1 cells. As underlying mechanisms, we found that the ALA–TLR4 axis stimulated both MyD88- and TRIF-mediated signaling pathways, whereas monophosphoryl lipid A was biased toward TRIF signaling. These findings revealed the effects of ALA on DCs and T cells and its induction pattern on signaling pathways.