A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

被引：11

作者：

Cook, Christopher P. ^{[1
,2
]}

Taylor, Mark ^{[1
,3
]}

Liu, Yale ^{[2
,4
]}

Schmidt, Ralf ^{[5
]}

Sedgewick, Andrew ^{[6
]}

Kim, Esther ^{[7
]}

Hailer, Ashley ^{[1
]}

North, Jeffrey P. ^{[1
]}

Harirchian, Paymann ^{[1
,2
]}

Wang, Hao ^{[8
]}

Kashem, Sakeen W. ^{[1
,2
]}

Shou, Yanhong ^{[9
]}

McCalmont, Timothy C. ^{[1
,10
,11
]}

Benz, Stephen C. ^{[6
]}

Choi, Jaehyuk ^{[12
]}

Purdom, Elizabeth ^{[8
]}

Marson, Alexander ^{[5
]}

Ramos, Silvia B. V. ^{[13
]}

Cheng, Jeffrey B. ^{[1
,2
]}

Cho, Raymond J. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94115 USA

[2] Vet Affairs Med Ctr, Dermatol, San Francisco, CA 94121 USA

[3] Med Univ Bialystok, Clin Res Ctr, Bialystok, Poland

[4] Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Dermatol, Xian 710004, Shaanxi, Peoples R China

[5] Gladstone UCSF Inst Genom Immunol, San Francisco, CA USA

[6] NantHlth Inc, El Segundo, CA USA

[7] Univ Calif San Francisco, Div Plast Surg, San Francisco, CA USA

[8] Univ Calif Berkeley, Dept Stat, Berkeley, CA USA

[9] Fudan Univ, Huashan Hosp, Dept Dermatol, Shanghai, Peoples R China

[10] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA

[11] Golden State Dermatol Associates, Walnut Creek, CA USA

[12] Northwestern Univ, Dept Dermatol, Evanston, IL USA

[13] Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC USA

来源：

CELL REPORTS MEDICINE | 2022年 / 3卷 / 08期

基金：

美国国家卫生研究院;

关键词：

TRISTETRAPROLIN; EXPRESSION; ASSOCIATION; PSORIASIS;

D O I：

10.1016/j.xcrm.2022.100715

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 inflam-mation-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 inter-leukin-17A (IL-17A), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon gamma (IFNg) elevation in psoriatic memory T cells deficient in these transcripts, functionally validating their influ-ence. Combinatoric expression analysis indicates the suppression of specific inflammatory mediators by in-dividual program members. Finally, we find that therapeutic IL-23 blockade reduces Th17/Tc17 cell fre-quency in lesional skin but fails to normalize this inflammatory-suppressive program, suggesting how treated lesions may be primed for recurrence after withdrawal of treatment.

引用

页数：20

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