IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants.
IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants.
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IL-18和囊下淋巴结巨噬细胞对于增强TLR4激动剂佐剂的B细胞反应至关重要。
DOI：
10.4049/jimmunol.1600993
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发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
Orr MT
中科院分区：
文献类型：
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作者：
Desbien AL;Dubois Cauwelaert N;Reed SJ;Bailor HR;Liang H;Carter D;Duthie MS;Fox CB;Reed SG;Orr MT
设计现代疫苗佐剂取决于了解连接先天免疫反应和适应性免疫反应的细胞和分子事件。合成的TLR4激动剂GLA在稳定乳液中配制（GLA- se）增强了对疫苗抗原的细胞和体液免疫反应。这种佐剂目前被包括在几种正在进行临床评估的疫苗中，包括用于结核病、利什曼病和流感的疫苗。对佐剂活性机制的描述将有助于对临床试验进行更翔实的评估。注射后早期，与明矾、单独的水角鲨烯乳液（SE）或不加SE的GLA相比，GLA-SE诱导的抗原特异性B细胞数量明显增加，血清抗体滴度更高，T滤泡辅助细胞（TFH）和TH1细胞数量也更多。GLA-SE增强抗原特异性B细胞分化为生发中心和记忆前体B细胞以及快速分泌抗体的前质母细胞。CD169+ SIGNR1+包膜下髓质巨噬细胞是免疫后吸收GLA-SE的主要细胞，对GLA-SE诱导的先天免疫应答（包括快速产生IL-18）至关重要。荚膜下巨噬细胞（scmφ）的损耗或IL-18信号的消除显著损害抗原特异性B细胞和GLA-SE增强的抗体反应。SCMϕ的损耗也会大大降低TH1响应，但不会降低TFH响应。因此，GLA-SE佐剂通过与产生il -18的SCMϕ相互作用来快速诱导B细胞的扩增和分化、抗体分泌和TH1反应，而GLA-SE对TFH数量的增加不依赖于SCMϕ。
Designing modern vaccine adjuvants depends on understanding the cellular and molecular events that connect innate and adaptive immune responses. The synthetic TLR4 agonist GLA formulated in a stable emulsion (GLA-SE) augments both cellular and humoral immune responses to vaccine antigens. This adjuvant is currently included in several vaccines undergoing clinical evaluation including those for tuberculosis, leishmaniasis, and influenza. Delineation of the mechanisms of adjuvant activity will enable more informative evaluation of clinical trials. Early after injection, GLA-SE induces substantially more antigen-specific B cells, higher serum antibody titers and greater numbers of T follicular helper (TFH) and TH1 cells than alum, the squalene-in-water emulsion (SE) alone, or GLA without SE. GLA-SE augments antigen-specific B cell differentiation into germinal center and memory precursor B cells as well as pre-plasmablasts that rapidly secrete antibodies. CD169+ SIGNR1+ subcapsular medullary macrophages are the primary cells to take up GLA-SE after immunization and are critical for the innate immune responses, including rapid IL-18 production, induced by GLA-SE. Depletion of subcapsular macrophages (SCMϕ) or abrogation of IL-18 signaling dramatically impairs the antigen-specific B cell and antibody responses augmented by GLA-SE. Depletion of SCMϕ also drastically reduces the TH1 but not TFH response. Thus the GLA-SE adjuvant operates through interaction with IL-18-producing SCMϕ for the rapid induction of B cell expansion and differentiation, antibody secretion and TH1 responses, whereas augmentation of TFH numbers by GLA-SE is independent of SCMϕ.