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

项目摘要 银屑病是最常见的免疫相关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和 加重慢性牛皮癣。人源化IL-12/IL-23 p40、IL-17A和IL-17受体单抗已显示 IL-23/IL-17轴在治疗慢性斑块型银屑病中的作用 在银屑病发病机制中的重要作用。我们之前的研究已经证明，皮肤γδT细胞是 皮肤中的主要IL-17生成物，在银屑病的发病机制中起关键作用。真皮γδT细胞 在表型和功能上都是独特的。然而，很大程度上还不清楚这些细胞是如何受到关键调控的。 小鼠和人类，特别是在微生物感染和皮肤微生物共生改变的背景下。 在这项提案中，我们提供了初步数据，表明真皮γδT细胞在皮肤中发挥着关键作用 免疫监视和炎症。IL-1β信号通路在调节真皮γδT细胞中的作用 细胞增殖，IL-17的产生，以及可能在老鼠体内的贩运。病原体产品刺激皮肤细胞 产生IL-1β。此外，我们还发现牛皮癣患者皮肤的微生物区系发生了很大的变化。 与健康对照皮肤相比。人Vγ9Vδ2T细胞能够分泌IL-17和 银屑病患者外周血显著下降，但在银屑病皮损和 产生大量的IL-17。根据这些初步发现，我们假设，失调的 真皮γδT细胞通过IL-1信号通过病原体感染或皮肤微生物区系改变发挥重要作用 在银屑病发病机制中的作用。针对这一假说，本文提出了三个目标。目标1决定了 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信号调节的假设 银屑病的免疫发病机制：1)直接激活皮肤γδT细胞；2)刺激KC分泌 趋化因子将更多产生IL-17的γδT细胞从外周吸引到真皮，从而放大 皮肤炎症级联反应；3)产生记忆样真皮γδT细胞，用于疾病复发。AIM 2考试 皮肤共生微生物如何调节健康皮肤和真皮γδT细胞动态平衡 皮肤炎症中的细胞激活。AIM 3确定人类Vγ9T细胞如何受病原体调节 成分或皮肤微生物区系的改变，以扩大和产生IL-17。人皮肤/SCID小鼠 将建立异种移植模型以确定人Vγ9T细胞和微生物的致病作用 银屑病发病机制中的感染/共生改变相信这项研究将提供新的见解。 了解皮肤γδT细胞群生物学及银屑病的免疫发病机制。

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.