O'Farrell Aoife, Niu Zijian, Li Jingxin, Van Eyndhoven Laura C, Sarma Kavitha, Raj Arjun
Department of Bioengineering, School of Engineering and Applied Sciences University of Pennsylvania, Philadelphia, PA, USA.
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
bioRxiv. 2025 Jan 24:2025.01.22.634275. doi: 10.1101/2025.01.22.634275.
Innate immune memory (also termed trained immunity) is defined in part by its ability to cross-protect against heterologous pathogens, and can be generated by many different stimuli, suggesting a "universal" trained state. However, different stimuli could form distinct memories, leading to stimulus-specific trained responses. Here, we use primary human monocyte-derived macrophages to demonstrate phenotypic and epigenetic stimulus specificity of innate immune memory six days after initial exposure. Quantification of cytokine production with single-molecule RNA imaging demonstrates stimulus-specific patterns of response to restimulation at the single cell level. Differential licensing of inflammatory transcription factors is associated with encoding of specificities in chromatin. Trained cells show stronger responses to secondary stimuli that are more similar to the initial stimulus they experienced, suggesting a functional role for these stimulus-specific memories. Rather than activating a universal training state, our findings demonstrate that different stimuli impart specific memories that generate distinct training phenotypes in macrophages.
固有免疫记忆（也称为训练免疫）部分由其对异源病原体的交叉保护能力来定义，并且可以由许多不同的刺激产生，这表明存在一种“通用”的训练状态。然而，不同的刺激可能形成不同的记忆，从而导致特定于刺激的训练反应。在这里，我们使用原代人单核细胞衍生的巨噬细胞来证明初始暴露六天后固有免疫记忆的表型和表观遗传刺激特异性。通过单分子RNA成像对细胞因子产生进行定量，揭示了单细胞水平上对再刺激的刺激特异性反应模式。炎症转录因子的差异许可与染色质中特异性的编码相关。受过训练的细胞对与它们最初经历的刺激更相似的二次刺激表现出更强的反应，表明这些刺激特异性记忆具有功能作用。我们的研究结果表明，不同的刺激赋予特定的记忆，这些记忆在巨噬细胞中产生不同的训练表型，而不是激活一种通用的训练状态。
