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

Cell Rep Med. 2022 Aug 16;3(8):100715. doi: 10.1016/j.xcrm.2022.100715.

Authors

Christopher P Cook¹, Mark Taylor², Yale Liu³, Ralf Schmidt⁴, Andrew Sedgewick⁵, Esther Kim⁶, Ashley Hailer⁷, Jeffrey P North⁷, Paymann Harirchian¹, Hao Wang⁸, Sakeen W Kashem¹, Yanhong Shou⁹, Timothy C McCalmont¹⁰, Stephen C Benz⁵, Jaehyuk Choi¹¹, Elizabeth Purdom⁸, Alexander Marson⁴, Silvia B V Ramos¹², Jeffrey B Cheng¹³, Raymond J Cho¹⁴

Affiliations

¹ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA.
² Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Clinical Research Centre, Medical University of Białystok, Białystok, Poland.
³ Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi 710004, P.R. China.
⁴ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
⁵ NantHealth, Inc, El Segundo, CA, USA.
⁶ Division of Plastic Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Statistics, University of California, Berkeley, Berkeley, CA, USA.
⁹ Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P.R. China.
¹⁰ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Golden State Dermatology Associates, Walnut Creek, CA, USA.
¹¹ Department of Dermatology, Northwestern University, Evanston, IL, USA.
¹² Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA. Electronic address: Jeffrey.Cheng@ucsf.edu.
¹⁴ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: raymond.cho@ucsf.edu.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Inflammation / metabolism
Inflammation Mediators / metabolism
Memory T Cells*
Skin / metabolism
Th17 Cells*

Substances

Inflammation Mediators

Grants and funding

T32 AR007175/AR/NIAMS NIH HHS/United States