Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States.
Department of Immunology, Harvard Medical School; and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, United States.
Elife. 2020 Aug 10;9:e58463. doi: 10.7554/eLife.58463.
T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an A-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and identified surrogate agonist peptides, with differing affinities and signaling potencies. The VAT-Treg cells expanded in vivo by one of the surrogate agonists preserved the typical VAT-Treg transcriptional programs. Immunization with this surrogate, especially when coupled with blockade of TNFα signaling, expanded VAT-Treg cells, resulting in protection from inflammation and improved metabolic indices, including promotion of insulin sensitivity. These studies suggest that antigen-specific targeting of VAT-localized Treg cells could eventually be a strategy for improving metabolic disease.
调节性 T（Treg）细胞在调节免疫和组织稳态方面发挥着重要作用。它们的作用依赖于 TCR 识别肽-MHC 分子；然而，Treg 细胞功能的肽特异性程度，以及 Treg 配体是否可用于操纵 Treg 细胞生物学尚不清楚。在这里，我们开发了一种 A 肽文库，该文库可用于对从内脏脂肪组织（VAT）中分离出的真正的鼠 Treg 细胞克隆识别的肽进行无偏筛选，并鉴定出具有不同亲和力和信号转导能力的替代激动肽。其中一种替代激动剂在体内扩增的 VAT-Treg 细胞保留了典型的 VAT-Treg 转录程序。用这种替代物进行免疫接种，特别是与阻断 TNFα 信号通路相结合，可扩增 VAT-Treg 细胞，从而防止炎症并改善代谢指标，包括促进胰岛素敏感性。这些研究表明，针对 VAT 定位的 Treg 细胞的抗原特异性靶向最终可能成为改善代谢疾病的一种策略。
