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 lesional skin, strikingly restricts Th17 cytokine other inflammatory mediators on level. have recently shown CRISPR-based deactivation core components this replicates elevated IL17F, IL26, IFNG cells deficient these transcripts, functionally validating their influence. Combinatoric expression analysis establishes dominant trajectory increasingly inflamed can also distinguish influence individual suppressive transcripts specific mediators. Finally, we find therapeutic IL23 blockade reduces frequency fails re-establish illustrating how treated lesions may be primed for recurrence upon withdrawal treatment.