Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS-CoV-2 mRNA vaccination primes human monocyte-derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3-driven pyroptotic cell death and subsequently secrete mature interleukin-1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C-type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage-driven activation of effector memory T cells. Furthermore, vaccination-induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime-boost concepts to augment innate immune signaling in SARS-CoV-2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein-specific T cell responses.

中文翻译：

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脾酪氨酸激酶介导 SARS-CoV-2 mRNA 疫苗接种中的先天性和适应性免疫串扰

持久的细胞介导的免疫反应需要有效的先天免疫信号和促炎细胞因子的释放。mRNA疫苗如何精确地触发先天免疫细胞以形成抗原特异性适应性免疫仍然未知。在这里，我们表明 SARS-CoV-2 mRNA 疫苗接种会引发人类单核细胞衍生的巨噬细胞激活 NLRP3 炎性体。暴露于刺突蛋白的巨噬细胞经历 NLRP3 驱动的细胞焦亡，随后分泌成熟的白细胞介素 1β。这些作用取决于与 C 型凝集素受体偶联的脾酪氨酸激酶 (SYK) 的激活。使用自体共培养，我们表明 SYK 和 NLRP3 协调巨噬细胞驱动的效应记忆 T 细胞的激活。此外，重复抗原暴露可以增强疫苗接种诱导的巨噬细胞启动，这为启动增强概念以增强 SARS-CoV-2 疫苗接种中的先天免疫信号传导提供了基本原理。总的来说，这些发现将 SYK 确定为能够区分引发和未引发巨噬细胞的调节节点，其调节刺突蛋白特异性 T 细胞反应。