人类皮肤记忆 T 细胞中的单细胞转录梯度限制了 Th17/Tc17 细胞的身份。
A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity.
机构信息
Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA.
Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Clinical Research Centre, Medical University of Białystok, Białystok, Poland.
出版信息
Cell Rep Med. 2022 Aug 16;3(8):100715. doi: 10.1016/j.xcrm.2022.100715.
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.
在一些疾病中，如寻常型银屑病，体内的稳态机制未能抑制慢性组织炎症，但目前仍不完全清楚其具体机制。我们对单个银屑病和正常皮肤驻留 T 细胞的转录组和表位进行了分析，揭示了一个协调调控炎症抑制基因的分级转录程序。该程序在皮损皮肤中受到明显抑制，在单细胞水平上显著限制了 Th17/Tc17 细胞因子和其他炎症介质的产生。基于 CRISPR 的方法对该炎症抑制程序的两个核心组件 ZFP36L2 和 ZFP36 进行失活，可复制缺乏这些转录本的银屑病记忆 T 细胞中白细胞介素 17A（IL-17A）、粒细胞巨噬细胞集落刺激因子（GM-CSF）和干扰素 γ（IFNγ）的升高，从而在功能上验证了它们的影响。组合表达分析表明，个体程序成员对特定炎症介质的抑制作用。最后，我们发现治疗性 IL-23 阻断可降低皮损皮肤中 Th17/Tc17 细胞的频率，但不能使这种炎症抑制程序恢复正常，这表明治疗后皮损可能会在停药后再次复发。
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