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

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

doi:10.1016/j.xcrm.2022.100715

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

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

University of California at San Francisco
Department of Veterans Affairs
Medical University of Białystok
The Second Affiliated Hospital of Xi'an Jiaotong University
Inc
University of California at Berkeley
Fudan University
Golden State Dermatology Associates
Northwestern University
University of North Carolina at Chapel Hill

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English
Article number	100715
Journal	Cell Reports Medicine
Volume	3
Issue number	8
DOIs	https://doi.org/10.1016/j.xcrm.2022.100715
State	Published - 16 Aug 2022
Externally published	Yes

Keywords

ZFP36
ZFP36L2
cytokine
inflammation
psoriasis
resident-memory T cell
tristetraprolin scRNA-seq

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10.1016/j.xcrm.2022.100715

Cite this

Cook, C. P., Taylor, M., Liu, Y., Schmidt, R., Sedgewick, A., Kim, E., Hailer, A., North, J. P., Harirchian, P., Wang, H., Kashem, S. W., Shou, Y., McCalmont, T. C., Benz, S. C., Choi, J., Purdom, E., Marson, A., Ramos, S. B. V., Cheng, J. B., & Cho, R. J. (2022). A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity. Cell Reports Medicine, 3(8), Article 100715. https://doi.org/10.1016/j.xcrm.2022.100715

@article{32a705348bfb4b249b3db8780d60f5ce,

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

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 = "ZFP36, ZFP36L2, cytokine, inflammation, psoriasis, resident-memory T cell, tristetraprolin scRNA-seq",

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

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = aug,

day = "16",

doi = "10.1016/j.xcrm.2022.100715",

language = "英语",

volume = "3",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "8",

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Cook, CP, Taylor, M, Liu, Y, Schmidt, R, Sedgewick, A, Kim, E, Hailer, A, North, JP, Harirchian, P, Wang, H, Kashem, SW, Shou, Y, McCalmont, TC, Benz, SC, Choi, J, Purdom, E, Marson, A, Ramos, SBV, Cheng, JB & Cho, RJ 2022, 'A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity', Cell Reports Medicine, vol. 3, no. 8, 100715. https://doi.org/10.1016/j.xcrm.2022.100715

TY - JOUR

T1 - A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

AU - Cook, Christopher P.

AU - Taylor, Mark

AU - Liu, Yale

AU - Schmidt, Ralf

AU - Sedgewick, Andrew

AU - Kim, Esther

AU - Hailer, Ashley

AU - North, Jeffrey P.

AU - Harirchian, Paymann

AU - Wang, Hao

AU - Kashem, Sakeen W.

AU - Shou, Yanhong

AU - McCalmont, Timothy C.

AU - Benz, Stephen C.

AU - Choi, Jaehyuk

AU - Purdom, Elizabeth

AU - Marson, Alexander

AU - Ramos, Silvia B.V.

AU - Cheng, Jeffrey B.

AU - Cho, Raymond J.

PY - 2022/8/16

Y1 - 2022/8/16

N2 - 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.

AB - 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.

KW - ZFP36

KW - ZFP36L2

KW - cytokine

KW - inflammation

KW - psoriasis

KW - resident-memory T cell

KW - tristetraprolin scRNA-seq

UR - https://www.scopus.com/pages/publications/85135917300

U2 - 10.1016/j.xcrm.2022.100715

DO - 10.1016/j.xcrm.2022.100715

M3 - 文章

C2 - 35977472

AN - SCOPUS:85135917300

SN - 2666-3791

VL - 3

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 8

M1 - 100715

ER -

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

Abstract

Keywords

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