Ligand-receptor hotspots in dendritic-T cell niches expose targets in autoimmunity

Dendritic cell-T cell (DC-T) co-signalling pathways are central switches directing immunity, tolerance, or evasion. Despite characterisation of known pathways, additional mediators that may contribute uniquely to regulating T-cell responses remain to be defined.

To identify emerging mediators of DC-T communication associated with autoimmune skin inflammation.

Spatial transcriptomic data from atopic dermatitis (AD) and psoriasis (PsO) skin were integrated with single-cell RNA sequencing to resolve ligand-receptor (LR) networks operating at DC-T interaction sites, including regions of DC-T co-occupation, defined as spots simultaneously enriched for DC and T-cell transcriptional signatures. LR-based ranking was used to prioritise canonical and emerging co-signalling mediators linked to autoimmune inflammation, which were subsequently validated in independent spatial and CITE-seq datasets.

Top-ranked genes F11R and CDH3 localised to the epidermis, an area enriched in highly interactive DC-T regions, and correlated with PsO severity, establishing a link between spatial communication strength and clinical outcome. Among these, F11R also associated with cytokine signalling in severe PsO, linking its spatial enrichment to enhanced inflammatory states within interaction-rich niches. CITE-seq analysis showed that F11R RNA and protein expression correlate in PsO patients, with no upregulation observed in circulating DCs or T cells. In contrast, both F11R and co-signalling molecules were elevated in the arthritic form of the disease, characterised by systemic immune activation.

This study establishes a spatial framework for identifying immune communication mediators and highlight F11R as a potential target linked to autoimmune skin inflammation severity.

Mapping dendritic-T cell communication in psoriasis identifies F11R as a spatially enriched signature associated with disease severity, offering insight into local immune amplification and highlighting potential targets for precision modulation of autoimmune inflammation.