Exploring mechanisms that govern immune homeostasis in skin

屏障破坏和经皮致敏是导致哮喘和食物过敏的特应性皮炎的主要病理过程，并且当通过皮肤递送时疫苗接种是最有效的。因此，皮肤免疫不仅对局部，而且对全身免疫都有很强的影响。此外，阐明基质细胞介导的免疫稳态应该对癌细胞如何调节或逃避免疫系统产生影响。皮肤中白细胞稳态和免疫反应的复杂调节的基本机制仍未得到充分研究。我们探索了皮肤免疫的以下重要方面：1）毛囊和其他基质细胞在调节皮肤驻留白细胞中的作用我们先前确定毛囊能够在感知应激时通过趋化因子产生来招募和调节皮肤树突状细胞的运输，首次建立了HF具有免疫功能。我们最近证明（Nature Medicine，2015）HF不仅招募树突状细胞，而且通过产生IL-7和IL-15支持皮肤中的常驻记忆T细胞持久性。CD 8 + T细胞依赖于HF衍生的IL-15，而CD 4+和CD 8 + T细胞都依赖于HF衍生的IL-7。我们进一步确定了一种新的恶性淋巴瘤与皮肤浸润的模型，常驻记忆T细胞表型的CD 4+淋巴瘤细胞浸润的HF-衍生的IL-7依赖的方式在皮肤。IL-7-IL-7受体轴在人皮肤恶性淋巴瘤中起作用。这些发现为设计新的治疗策略提供了临床意义，这些治疗策略靶向皮肤恶性淋巴瘤或由驻留记忆T细胞介导的其他炎症性皮肤病中的IL-7或IL-7受体信号传导。我们正在对皮肤中的各种白细胞亚群进行更广泛的研究，并正在探索通过与毛囊和其他基质细胞亚群相互作用来管理其驻留的机制。2)已知金黄色葡萄球菌在人类特应性皮肤中定植，但这是否是皮肤炎症的原因或仅仅是慢性炎症的结果一直存在争议。我们最近开发了一种小鼠模型，在该模型中，小鼠表现出与特应性皮炎特征非常相似的湿疹性皮炎，并且经历了自然发生的由S。金黄色葡萄球菌和棒状杆菌属（Immunity，2015）。通过抗生素鸡尾酒靶向微生态失调的植物群对湿疹性皮炎具有预防和治疗作用，特别是保护了微生物多样性。S. aureus主要驱动皮肤炎症，而C.牛增强了辅助性T细胞2应答，这可能导致血清中IgE升高。表皮生长因子受体信号传导受损导致菌群失调，表皮朗格汉斯细胞启动了针对链球菌的先天性免疫反应。金黄色。这些结果鉴定了S.金黄色葡萄球菌作为湿疹形成的关键成分，并为开发新的治疗策略提供了启示。对生态失调下游免疫途径的研究正在进行中。

Barrier disruption and percutaneous sensitization are major pathological processes in atopic dermatitis that lead to asthma and food allergy, and vaccination is most efficacious when delivered via skin. Thus, skin immunity has strong impact not only the local, but also on systemic immunity. Furthermore, elucidating stromal cell-mediated immune homeostasis should have impact on how cancer cells regulate or evade the immune system. Fundamental mechanisms that underlie intricate regulation of leukocyte homeostasis and immune responses in skin remain understudied. We explore the below important aspects of skin immunity: 1) The role of hair follicles and other stromal cells in regulating skin-resident leukocytes We previously determined that hair follicles are capable of recruiting and regulating the trafficking of skin dendritic cells via chemokine production upon sensing stress, establishing for the first time that the HF are immunologically functional. We have recently demonstrated (Nature Medicine, 2015) that not only do HF recruit dendritic cells, but they also support resident memory T cell persistence in skin by producing IL-7 and IL-15. CD8+ T cells were dependent on HF-derived IL-15 and both CD4+ and CD8+ T cells were dependent on HF-derived IL-7. We further determined in a novel model for malignant lymphoma with skin infiltration that CD4+ lymphoma cells of resident memory T cell phenotype infiltrate the skin in HF-derived IL-7-dependent manner. The IL-7-IL-7 receptor axis appears to be operation in human malignant lymphoma of the skin. These findings provide clinical implications for designing new therapeutic strategies that target IL-7 or IL-7 receptor signaling in malignant lymphoma in the skin or other inflammatory skin diseases mediated by resident memory T cells. We are in the process of gaining a broader view on the various leukocyte subsets that reside in the skin and are exploring the mechanisms that govern their residency by interacting with not only hair follicles but also other stromal cell subsets. 2) Mechanisms of microbiota-driven eczematous inflammation in mice Staphylococcus aureus has been known to colonize atopic skin in humans, but whether this was the cause of skin inflammation or merely a result of chronic inflammation had been long debated. We recently developed a model in which mice exhibit eczematous dermatitis that closely resembles features of atopic dermatitis and that undergoes naturally occurring dysbiosis consisting of S. aureus and Corynebacterium species (Immunity, 2015). Targeting dysbiotic flora via an antibiotic cocktail had both preventive and therapeutic effects on eczematous dermatitis, and notably, conserved microbial diversity. S. aureus primarily drove skin inflammation, whereas C. bovis enhanced T helper 2 responses that likely lead to elevated IgE in serum. Dysbiosis occurred as a result of impaired EGFR-signaling and epidermal Langherhans cells initiated innate immune responses against S. aureus. These results identified S. aureus as a critical component in eczema formation and provides implication for developing novel therapeutic strategies. Studies on immunological pathways downstream of dysbiosis are underway.