Department of Biosciences, University of Salzburg, Salzburg, Austria.
Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria.
Sci Rep. 2020 Jul 7;10(1):11164. doi: 10.1038/s41598-020-67430-7.
Human skin contains a population of memory T cells that supports tissue homeostasis and provides protective immunity. The study of human memory T cells is often restricted to in vitro studies and to human PBMC serving as primary cell source. Because the tissue environment impacts the phenotype and function of memory T cells, it is crucial to study these cells within their tissue. Here we utilized immunodeficient NOD-scid IL2rγ (NSG) mice that carried in vivo-generated engineered human skin (ES). ES was generated from human keratinocytes and fibroblasts and was initially devoid of skin-resident immune cells. Upon adoptive transfer of human PBMC, this reductionist system allowed us to study human T cell recruitment from a circulating pool of T cells into non-inflamed human skin in vivo. Circulating human memory T cells preferentially infiltrated ES and showed diverse functional profiles of T cells found in fresh human skin. The chemokine and cytokine microenvironment of ES closely resembled that of non-inflamed human skin. Upon entering the ES T cells assumed a resident memory T cell-like phenotype in the absence of infection, and a proportion of these cutaneous T cells can be locally activated upon injection of monocyte derived dendritic cells (moDCs) that presented Candida albicans. Interestingly, we found that CD69 memory T cells produced higher levels of effector cytokines in response to Candida albicans, compared to CD69 T cells. Overall, this model has broad utility in many areas of human skin immunology research, including the study of immune-mediated skin diseases.
人类皮肤中存在一群记忆 T 细胞，它们支持组织稳态并提供保护性免疫。对人类记忆 T 细胞的研究通常受到限制，只能在体外研究和以人类 PBMC 作为主要细胞来源。由于组织环境会影响记忆 T 细胞的表型和功能，因此在其组织内研究这些细胞至关重要。在这里，我们利用携带体内生成的工程化人类皮肤（ES）的免疫缺陷型 NOD-scid IL2rγ（NSG）小鼠。ES 由人类角质形成细胞和成纤维细胞生成，最初缺乏皮肤常驻免疫细胞。在过继转移人类 PBMC 后，这个简化系统使我们能够研究循环 T 细胞池中人类 T 细胞从循环池中招募到体内非炎症性人类皮肤中的情况。循环中的人类记忆 T 细胞优先浸润 ES，并表现出与新鲜人类皮肤中发现的 T 细胞多样化的功能谱。ES 的趋化因子和细胞因子微环境与非炎症性人类皮肤非常相似。进入 ES 后，T 细胞在没有感染的情况下呈现出类似于驻留记忆 T 细胞的表型，并且在注射呈递白色念珠菌的单核细胞衍生树突细胞（moDC）后，其中一部分皮肤 T 细胞可以被局部激活。有趣的是，我们发现与 CD69 T 细胞相比，CD69 记忆 T 细胞在响应白色念珠菌时产生更高水平的效应细胞因子。总的来说，该模型在人类皮肤免疫学研究的许多领域具有广泛的应用，包括免疫介导性皮肤病的研究。
