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

Informazioni relative al progetto

ImmGenDC

ID dell’accordo di sovvenzione: 101076303

DOI

10.3030/101076303

Data della firma CE 17 Agosto 2023

Data di avvio 1 Ottobre 2023

Data di completamento 30 Settembre 2028

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 499 235,00

Contributo UE

€ 1 499 235,00

Coordinato da

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany

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

Periodo di rendicontazione: 2023-10-01 al 2026-03-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.