조재현 (UCSF Department of Dermatology)

한빛사논문

조회223

UCSF Department of Dermatology

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Cell Rep. Med., Aug 16 2022, 3 (8) 100715 S2666-3791(22)00258-0 | https://doi.org/10.1016/j.xcrm.2022.100715 A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

Christopher P. Cook^{1 2 14}, Mark Taylor ^{1 3 14}, Yale Liu^{2 4 14}, Ralf Schmidt ⁵, Andrew Sedgewick ⁶, Esther Kim ⁷, Ashley Hailer ¹, Jeffrey P. North ¹, Paymann Harirchian ^{1 2}, Hao Wang ⁸, Sakeen W. Kashem ^{1 2}, Yanhong Shou ⁹, Timothy C. McCalmont ^{1 10 11}, Stephen C. Benz ⁶, Jaehyuk Choi ¹², Elizabeth Purdom ⁸, Alexander Marson ⁵, Silvia B.V. Ramos ¹³, Jeffrey B. Cheng ¹ ^{2 15 *}, Raymond J. Cho ^{1 15 16 *}

¹Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA

²Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA

³Clinical Research Centre, Medical University of Białystok, Białystok, Poland

⁴Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ShaanXi 710004, P.R. China

⁵Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA

⁶NantHealth, Inc, El Segundo, CA, USA

⁷Division of Plastic Surgery, University of California, San Francisco, San Francisco, CA, USA

⁸Department of Statistics, University of California, Berkeley, Berkeley, CA, USA

⁹Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P.R. China

¹⁰Department of Pathology, University of California, San Francisco, San Francisco, CA, USA

¹¹Golden State Dermatology Associates, Walnut Creek, CA, USA

¹²Department of Dermatology, Northwestern University, Evanston, IL, USA

¹³Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

¹⁴These authors contributed equally

¹⁵Senior author

¹⁶Lead contact

^*Corresponding authors: correspondence to Jeffrey B. Cheng or Raymond J. Cho

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.

논문정보

형식Research article
게재일2022년 08월 (BRIC 등록일 2024-01-31)
연구진국외 연구진
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