Fergusson Joannah R, Siu Jacqueline H Y, Gupta Nitya, Jenkins Edward, Nee Eloise, Reinke Sören, Ströbel Tamara, Bhalla Ananya, Kandage Shyami M, Courant Thomas, Hill Sarah, Attar Moustafa, Dustin Michael L, Gordon-Weeks Alex, Coles Mark, Dendrou Calliope A, Milicic Anita
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Cell Rep. 2025 Jul 22;44(7):115938. doi: 10.1016/j.celrep.2025.115938. Epub 2025 Jul 2.
Immunological processes that underpin human immune responses to therapeutics and vaccine components, such as vaccine adjuvants, remain poorly defined due to a paucity of models that faithfully recapitulate immune activation in lymphoid tissues. We describe precision-cut human lymph node (LN) slices as a functioning, architecturally preserved, full-organ cross-sectional model system. Using single-cell transcriptomics and multiplexed imaging, we explore early inflammatory response to a potent, clinically relevant liposomal vaccine adjuvant containing a TLR4-agonist and QS-21 saponin. Both TLR4 and NLRP3 inflammasome activation are involved in the direct initiation of the inflammatory response to adjuvant by monocytes and macrophages (Mon./Mac.) with secretion of interleukin (IL)-1β, but not IL-18, dependent on TLR4 signaling. Innate lymphoid cells, including natural killer cells, are indirectly activated by Mon./Mac.-produced cytokines, signaling downstream to B cells via interferon-γ secretion. Resident LN stromal populations, primed both directly and indirectly by vaccine adjuvant, are instrumental in mediating inflammatory cell recruitment, particularly neutrophils.
由于缺乏能在淋巴组织中如实地重现免疫激活的模型，支撑人类对治疗药物和疫苗成分（如疫苗佐剂）免疫反应的免疫过程仍未得到充分阐明。我们将精确切割的人类淋巴结（LN）切片描述为一种功能正常、结构保存完好的全器官横截面模型系统。利用单细胞转录组学和多重成像技术，我们研究了对一种含有TLR4激动剂和QS-21皂苷的强效、临床相关脂质体疫苗佐剂的早期炎症反应。TLR4和NLRP3炎性小体激活均参与单核细胞和巨噬细胞（Mon./Mac.）对佐剂炎症反应的直接启动，并分泌白细胞介素（IL）-1β，但不分泌IL-18，这依赖于TLR4信号传导。包括自然杀伤细胞在内的固有淋巴细胞被Mon./Mac.产生的细胞因子间接激活，并通过干扰素-γ分泌向下游B细胞发出信号。疫苗佐剂直接和间接激活的驻留LN基质群体有助于介导炎症细胞募集，尤其是中性粒细胞。
