Dissecting the context-specificity of genetic immune regulation in plasmacytoid dendritic cells

Antiviral immunity and autoimmune diseases exhibit high interindividual variability. Despite intensive research, the genetic and molecular basis of this variability is incompletely understood. A key player of the immune system is the plasmacytoid dendritic cell(pDC). Recent single-cell work revealed functionally distinct pDC subsets. Considering that pDCs respond to many pathogens, this highlights a previously underappreciated functional diversity of pDCs.I hypothesize that the genetic regulation of pDCs plays a fundamental role in explaining antiviral response and autoimmune variability. Based on my previous work on immune cells, this genetic regulation is expected to be highly context-specific depending on cell type, cell response, ancestry populations and sex among other factors.The overarching goal of this proposal is to elucidate the context-specificity of immune response and its genetic regulation in pDCs to improve our understanding of human antiviral response variation and pinpoint undiscovered disease pathways of autoimmune diseases.To this end, I will generate population-scale, linked scATAC-, sc3’RNA- and scLong-read cDNA-seq data of baseline and TLR7-stimulated pDCs from healthy individuals across three ancestry populations. I will identify novel pDC subtypes and their immune-regulatory circuits by integrated multiome analyses. Molecular quantitative trait loci(QTLs) and their degree of context-specificity will be used to build prediction models of genetically determined immune responsiveness and decode autoimmune disease loci to develop mechanistically anchored interventions for precision medicine.ImmGenDC will gain fundamental insights into the variability of antiviral immune response that will enable the development of new treatments as exemplified by the current pandemic. Importantly, ImmGenDC will also identify genetic determinants of immune variability across diverse ancestry populations thus paving the way for equitable access to medicine.