A Single-Cell Transcriptional Gradient in Human Cutaneous Memory T Cells Restricts Th17/Tc17 Identity

Authors

Christopher P Cook
Mark Taylor
Yale Liu
Ralf Schmidt
Andrew Sedgewick
Esther Kim
Ashley Hailer
Jeffrey P North
Paymann Harirchian
Hao Wang
Sakeen W Kashem
Yanhong Shou
Timothy C McCalmont
Stephen C Benz
Jaehyuk Choi
Elizabeth Purdom
Alexander Marson
Silvia B V Ramos
Jeffrey B Cheng
Raymond J Cho

Language

English

Publication Date

8-16-2022

Journal

Cell Reports Methods

DOI

10.1016/j.xcrm.2022.100715

PMID

35977472

PMCID

PMC9418858

PubMedCentral® Posted Date

8-16-2022

PubMedCentral® Full Text Version

Post-print

Abstract

The homeostatic mechanisms that fail to restrain chronic tissue inflammation in diseases, such as psoriasis vulgaris, remain incompletely understood. We profiled transcriptomes and epitopes of single psoriatic and normal skin-resident T cells, revealing a gradated transcriptional program of coordinately regulated inflammation-suppressive genes. This program, which is sharply suppressed in lesional skin, strikingly restricts Th17/Tc17 cytokine and other inflammatory mediators on the single-cell level. CRISPR-based deactivation of two core components of this inflammation-suppressive program, ZFP36L2 and ZFP36, replicates the interleukin-17A (IL-17A), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon gamma (IFNγ) elevation in psoriatic memory T cells deficient in these transcripts, functionally validating their influence. Combinatoric expression analysis indicates the suppression of specific inflammatory mediators by individual program members. Finally, we find that therapeutic IL-23 blockade reduces Th17/Tc17 cell frequency in lesional skin but fails to normalize this inflammatory-suppressive program, suggesting how treated lesions may be primed for recurrence after withdrawal of treatment.

Keywords

Humans, Inflammation, Inflammation Mediators, Memory T Cells, Skin, Th17 Cells, ZFP36L2, ZFP36, psoriasis, inflammation, resident-memory T cell, tristetraprolin scRNA-seq, cytokine

Published Open-Access

yes

Recommended Citation

Cook, Christopher P; Taylor, Mark; Liu, Yale; et al., "A Single-Cell Transcriptional Gradient in Human Cutaneous Memory T Cells Restricts Th17/Tc17 Identity" (2022). Staff and Researcher Publications. 19.
https://digitalcommons.library.tmc.edu/clinic_pub/19