Impact of rare JAK/STAT germline mutations on vaccination-induced innate immune responses in a Tyrolian population

Vaccination triggers the release of pro-inflammatory cytokines, the stimulation of the Janus Kinase (JAK) - Signal Transducer and Activator of Transcription (STAT) pathway and the activation of interferon response genes. While some JAK/STAT variants are associated with hematopoietic malignancies, the impact of the vast majority is unknown. Here we identify JAK/STAT germline variants in a Tyrolian cohort, including octogenarians, and link specific rare variants to enhanced vaccine-induced interferon transcriptomic responses. AlphaFold 3 predicted conformational changes in JAK and STATs variants, impacting their interactions and formation of receptor complexes. We also identified co-occurring variants in TYK2 and other modulators of interferon signaling that possibly modify the impact of JAK and STAT variants in the innate immune response. Our results demonstrate that the vaccine-induced innate immune transcriptomic response can be used for an <i>in vivo</i> functional assessment of mutations controlling key genetic pathways in the innate immune response.