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

Projektinformationen

ImmGenDC

ID Finanzhilfevereinbarung: 101076303

DOI

10.3030/101076303

EK-Unterschriftsdatum 17 August 2023

Startdatum 1 Oktober 2023

Enddatum 30 September 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 499 235,00

EU-Beitrag

€ 1 499 235,00

Koordiniert durch

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany

Periodic Reporting for period 1 - ImmGenDC (Dissecting the context-specificity of genetic immune regulation in plasmacytoid dendritic cells)

Berichtszeitraum: 2023-10-01 bis 2026-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Antiviral immunity and autoimmune diseases exhibit high interindividual variability. Despite intensive research, the genetic and molecular basis of this variability are incompletely understood. A key player of the immune system is the plasmacytoid dendritic cell (pDC). Recent single-cell (sc) work revealed functionally distinct pDC subsets. Considering that pDCs respond to many pathogens, this highlights a previously underappreciated functional diversity of pDCs. The overarching goal of ImmGenDC is to uncover, for the first time, the context-specificity of immune response and its genetic regulation in plasmacytoid dendritic cells at unprecedented scale and depth to improve our understanding of human antiviral immune variation and pinpoint undiscovered disease pathways of autoimmune diseases.
For this purpose, ImmGenDC generates population-scale, linked scATAC-, sc3’RNA- and scLong-read cDNA-seq data of baseline and TLR7-stimulated pDCs from healthy individuals across ancestry populations. Using integrated multiome analyses novel pDC subtypes and their immune-regulatory circuits are identified. 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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

we used two cutting edge single-cell technologies to characterise human pDC diversity with high resolution and breadth. Through scMultiome profiling (scATAC- and scRNA-seq of the same cells) and multimodal gene regulatory network analysis, we identified novel transcription factors as a potential regulators of type I IFN induction in human pDCs. Further, full-length transcript quantification via scLong-read RNA-seq revealed enhanced resolution of pDC diversity highlighting transcript diversity as a critical layer of gene regulation in human pDCs.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

ImmGenDC gains 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 identify genetic determinants of immune variability across diverse ancestry populations thus paving the way for equitable access to medicine.