Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasis

健康和牛皮癣中微生物病原体/共生体对真皮 γδ T 细胞的调节

• 批准号: 9245140
• 负责人: JUN YAN
• 金额: $ 20万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-20 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245140
• 关键词: Address; Biology; CCL20 gene; Cell Proliferation; Cells; Chronic; Chronic small plaque psoriasis; Clinical; Data; Dermal; Dermis; Development; Disease; Health; Homeostasis; Human; Immune; Immunologic Surveillance; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-12; Interleukin-17; Interleukins; Laboratories; Leukocytes; Memory; Modeling; Mus; Pathogenesis; Pathogenicity; Patients; Phase II Clinical Trials; Phenotype; Play; Population; Production; Psoriasis; Recurrent disease; Regulation; Role; SCID Mice; Signal Pathway; Signal Transduction; Skin; Source; Streptococcal Infections; Symbiosis; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Treatment Efficacy; Xenograft Model; base; chemokine; chronic inflammatory skin; cytokine; individual patient; insight; interleukin-23; keratinocyte; microbial; microorganism; neglect; novel; pathogen; peripheral blood; receptor; skin disorder; skin lesion; skin microbiota; trafficking; γδ T cells

Project Summary Psoriasis is one of the most common immune-related chronic inflammatory skin disorders. Clinical observations suggest that streptococcal infection has an intimate relationship in triggering psoriasis onset and exacerbating chronic psoriasis. Humanized IL-12/IL-23 p40, IL-17A, and IL-17 receptor mAbs have shown remarkable therapeutic efficacy for the treatment of chronic plaque psoriasis, suggesting IL-23/IL-17 axis plays important roles in psoriasis pathogenesis. Our previous studies have demonstrated that dermal γδ T cells are the major IL-17 producers in the skin and are critical in psoriasis pathogenesis. Dermal γδ T cells are phenotypically and functionally unique. However, it is largely unknown how these cells are critically regulated in mice and humans, particularly in the context of microbial infection and skin microbial commensal alteration. In the proposal, we provided preliminary data suggesting that dermal γδ T cells play critical roles in skin immune surveillance and inflammation. IL-1β signaling pathway plays a crucial role in regulating dermal γδ T cell proliferation, IL-17 production, and probably trafficking in mice. Pathogen products stimulated skin cells to produce IL-1β. In addition, we showed that skin microbiota from psoriatic skin has been substantially altered compared to that in healthy control skin. Human Vγ9Vδ2 T cells were capable of secreting IL-17 and significantly decreased in the peripheral blood of psoriatic patients but increased in psoriatic skin lesions and produced large amounts of IL-17. Based on these preliminary findings, we hypothesize that dysregulated dermal γδ T cells via IL-1 signaling by pathogen infection or skin microbiota alteration play an essential role in psoriasis pathogenesis. Three Aims are proposed to address this hypothesis. Aim 1 determines the role of IL-1 signaling in psoriasis immunopathogenesis. We will test the hypothesis that IL-1 signaling regulates psoriasis immunopathogenesis through 1) directly activating dermal γδ T cells; 2) stimulating KC to secrete chemokines which chemoattract more IL-17-producing γδ T cells from periphery into dermis thus amplifying skin inflammatory cascade; 3) generating memory-like dermal γδ T cells for disease relapse. Aim 2 examines how skin commensal microorganisms regulate dermal γδ T cell homeostasis in healthy skins and dermal γδ T cell activation in skin inflammation. Aim 3 determines how human Vγ9 T cells are regulated by pathogen components or skin microbiota alteration for expansion and IL-17 production. Human skin/SCID mouse xenograft model will be established to determine the pathogenic roles of human Vγ9 T cells and microbial infection/commensal alteration in psoriasis pathogenesis. It is believed that this study will provide new insights into understanding the biology of dermal γδ T cell population and immuno-pathogenesis of psoriasis.

项目摘要 银屑病是最常见的免疫相关性慢性炎症性皮肤病之一。临床 观察表明链球菌感染与银屑病的发病有密切关系， 加重慢性银屑病。人源化IL-12/IL-23 p40、IL-17 A和IL-17受体mAb已经显示出 对于治疗慢性斑块型银屑病疗效显著，提示IL-23/IL-17轴发挥作用 在银屑病发病机制中的重要作用。我们以前的研究表明，真皮γδ T细胞是 皮肤中主要的IL-17产生者，在银屑病发病机制中至关重要。真皮γδ T细胞是 表型和功能独特。然而，在很大程度上还不清楚这些细胞在体内是如何受到关键调控的。 小鼠和人，特别是在微生物感染和皮肤微生物组织改变的情况下。 在该提案中，我们提供了初步数据，表明真皮γδ T细胞在皮肤中发挥关键作用， 免疫监视和炎症。IL-1β信号通路在调节真皮γδ T中起重要作用 细胞增殖、IL-17产生以及可能在小鼠中的运输。病原体刺激皮肤细胞， 产生IL-1β。此外，我们发现银屑病皮肤的皮肤微生物群已经发生了实质性的改变， 与健康对照皮肤相比。人Vγ 9VS 2 T细胞能够分泌IL-17和IL-18。 在银屑病患者外周血中显著降低，但在银屑病皮损中增加， 产生大量的IL-17。基于这些初步发现，我们假设， 真皮γδ T细胞通过病原体感染或皮肤微生物群改变引起的IL-1信号传导， 银屑病的发病机制。提出了三个目标来解决这个假设。目标1确定了 IL-1信号在银屑病免疫发病机制中的作用。我们将检验IL-1信号调节 银屑病免疫发病机制通过1）直接激活真皮γδ T细胞; 2）刺激KC分泌 趋化因子将更多产生IL-17的γδ T细胞从外周吸引到真皮中，从而扩增 皮肤炎症级联反应; 3）产生记忆样真皮γδ T细胞用于疾病复发。目标2检查 皮肤微生物如何调节健康皮肤中真皮γδ T细胞稳态和真皮γδ T 皮肤炎症中的细胞活化。目的3确定病原体如何调节人Vγ9 T细胞 用于扩增和IL-17产生的组分或皮肤微生物群改变。人皮肤/SCID小鼠 将建立异种移植模型以确定人Vγ9 T细胞和微生物的致病作用。 银屑病发病机制中感染/皮肤改变。相信这项研究将为我们提供新的见解 了解真皮γδ T细胞群的生物学和银屑病的免疫发病机制。