509 A Single-Cell Transcriptional Gradient in Human Cutaneous Memory T Cells Suppresses Pathogenic Th17 Inflammation

Cutaneous psoriasis improves with targeted pathway inhibition, but the homeostatic mechanisms that normally restrain chronic tissue inflammation remain incompletely understood. We single-cell profiled human psoriatic and normal skin resident memory T cell transcriptomes to reveal a gradated transcriptional program of coordinately regulated inflammation-suppressive genes. This program, which is sharply suppressed in psoriatic lesional skin, strikingly restricts Th17 cytokine and other inflammatory mediators on the single-cell level. We have recently shown CRISPR-based deactivation of core components of this inflammation-suppressive program replicates the elevated IL17F, IL26, and IFNG in psoriatic memory T cells deficient in these transcripts, functionally validating their influence. Combinatoric expression analysis establishes a dominant single-cell trajectory of increasingly inflamed psoriatic resident memory T cells but can also distinguish the influence of individual suppressive program transcripts on specific inflammatory mediators. Finally, we find that therapeutic IL23 blockade reduces Th17 cell frequency in psoriatic skin but fails to re-establish expression of this inflammation-suppressive transcriptional program, illustrating how treated lesions may be primed for recurrence upon withdrawal of treatment.