Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination.
Sebastian J Theobald, Alexander Simonis, Julie M Mudler, Ulrike Göbel, Richard Acton, Viktoria Kohlhas, Marie-Christine Albert, Anna-Maria Hellmann, Jakob J Malin, Sandra Winter, Michael Hallek, Henning Walczak, Phuong-Hien Nguyen, Manuel Koch, Jan Rybniker
Author Information
Sebastian J Theobald: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.
Alexander Simonis: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
Julie M Mudler: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
Ulrike Göbel: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Richard Acton: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. ORCID
Viktoria Kohlhas: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
Marie-Christine Albert: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Anna-Maria Hellmann: Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Cologne, Germany.
Jakob J Malin: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
Sandra Winter: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.
Michael Hallek: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.
Henning Walczak: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. ORCID
Phuong-Hien Nguyen: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
Manuel Koch: Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
Jan Rybniker: Department I of Internal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany. ORCID
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.
