Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS‐CoV‐2 mRNA vaccination

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. Synopsis Innate immune signalling in monocytes following SARS‐CoV‐2 mRNA vaccination is not well understood. This study reports that macrophages isolated from vaccinated individuals participating in a longitudinal study undergo NLRP3 inflammasome activation upon re‐exposure to the SARS‐CoV‐2 spike protein (S‐protein). SARS‐CoV‐2 vaccination leads to macrophage reprogramming and phosphorylation of the spleen tyrosine kinase (SYK). Stimulation of macrophages with the S‐protein activates the NLRP3 inflammasome via SYK coupled to C‐type lectins. Macrophage SYK, NLRP3 and interleukin‐β are required for autologous T cell activation following vaccination. Booster vaccinations potently prime macrophages for Interleukin‐β secretion and pyroptosis. Graphical Abstract Innate immune signalling in monocytes following SARS‐CoV‐2 mRNA vaccination is not well understood. This study reports that macrophages isolated from vaccinated individuals participating in a longitudinal study undergo NLRP3 inflammasome activation upon re‐exposure to the SARS‐CoV‐2 spike protein (S‐protein).