CXCL9, CXCL10, and CCL19 synergistically recruit T lymphocytes to skin in lichen planus.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Anna E Kersh, Satish Sati, Jianhe Huang, Christina Murphy, Olivia Ahart, Thomas H Leung
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引用次数: 0

Abstract

Lichen planus (LP) is a chronic, debilitating, inflammatory disease of the skin and mucous membranes that affects 1%-2% of Americans. Its molecular pathogenesis remains poorly understood, and there are no FDA-approved treatments. We performed single-cell RNA sequencing on paired blood and skin samples (lesional and nonlesional tissue) from 7 patients with LP. We discovered that LP keratinocytes and fibroblasts specifically secrete a combination of CXCL9, CXCL10, and CCL19 cytokines. Using an in vitro migration assay with primary human T cells, we demonstrated that CCL19 in combination with either of the other 2 cytokines synergistically enhanced recruitment of CD8+ T cells more than any individual cytokine. Moreover, exhausted T cells in lesional LP skin secreted CXCL13, which, along with CCL19, also enhanced recruitment of T cells, suggesting a feed-forward loop in LP. Finally, LP blood revealed decreased circulating naive CD8+ T cells compared with that in healthy volunteers, consistent with recruitment to skin. Molecular analysis of LP skin and blood samples increased our understanding of disease pathogenesis and identified CCL19 as a new therapeutic target for treatment.

CXCL9、CXCL10 和 CCL19 在扁平苔藓患者的皮肤上协同招募 T 淋巴细胞。
扁平苔藓(LP)是一种慢性、使人衰弱的皮肤和粘膜炎症性疾病,1% 到 2% 的美国人患有此病。人们对这种疾病的分子发病机制仍然知之甚少,而且目前还没有获得美国食品及药物管理局批准的治疗方法。我们对 7 名 LP 患者的配对血液和皮肤样本(病变组织和非病变组织)进行了单细胞 RNA 测序。我们发现 LP 角质细胞和成纤维细胞会特异性分泌 CXCL9、CXCL10 和 CCL19 细胞因子。通过使用原代人类 T 细胞进行体外迁移试验,我们发现 CCL19 与其中任何一种细胞因子结合使用,都能协同增强 CD8 T 细胞的募集,其效果超过单个细胞因子的总和。此外,LP 病变皮肤中衰竭的 T 细胞会分泌 CXCL13,而 CXCL13 与 CCL19 也会增强 T 细胞的募集,这表明在 LP 中存在一个前馈循环。最后,与健康志愿者相比,LP患者的血液显示循环中的幼稚CD8 T细胞减少,这与皮肤的招募一致。对 LP 皮肤和血液样本的分子分析增加了我们对疾病发病机制的了解,并确定 CCL19 为新的治疗靶点。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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