Phd in HUMAN BIOLOGY AND MEDICAL GENETICS

Thesis title: The Role of Platelets in Innate and Adaptive Immunity: IBD and Vaccination as models to study the Platelet-Immune crosstalk

Platelets are known to have numerous functions that go beyond their canonical roles in hemostasis and thrombosis. Increasing evidence shows that platelets play an active role in modulating both innate and adaptive immune responses. However, the molecular mechanisms underlying platelet–immune crosstalk remain only partially understood. In this thesis work, we used vaccination and inflammatory bowel disease as models to study platelet–leukocyte crosstalk under physiological and pathological conditions, respectively. Under pathological conditions, we show that selective inhibition of the transcription factor NFAT (Nuclear Factor of Activated T Cells) in platelets leads to increased formation of Neutrophil Extracellular Traps (NETs) and, unexpectedly, confers protection in a murine model of experimental colitis. We further characterized this crosstalk by independently inhibiting NET formation and platelet activation, thereby demonstrating and confirming their detrimental roles in contrast to what was observed in the aforementioned genetic model. Under physiological conditions, we investigated platelet–adaptive immunity interactions in the context of influenza vaccination in a pediatric cohort, showing increased formation of platelet–B cell aggregates and a remodeling of the platelet surface phenotype before and after vaccination. Finally, we employed different murine models of platelet depletion during mRNA vaccination to study this crosstalk in vivo, revealing distinct trends in antibody formation and B cell–dependent immune responses depending on the method and kinetics of platelet depletion. In conclusion, our study demonstrates that complex interactions between platelets and leukocytes exist in vivo under both physiological and pathological conditions.