摘要：This article aims to provide a broad coverage of over 300 studies on T helper 17 (Th17) cells published mainly between 2011 and 2016, with a focus on factors negatively regulating Th17 cell differentiation and functions. During the last decade, processes underlying Th17 cell differentiation and activation, as well as Th17-specific cytokines, chemokines, and transcription factors, have been characterized. Diverse modalities controlling Th17 cells range from factors modulating the state of regulatory T (Treg) cells or dendritic cells and indirectly regulating Th17 cells to cell-intrinsic factors, such as those that repress genes encoding Th17 signature cytokines, including artificial products. Since IL-17 is a major player in tissue-specific immune pathology, Th17 cells, a major source of the cytokine, have been a subject of intensive research and have been at the forefront of clinical studies. New approaches, including conditional knockout mice as well as transcriptome profiling, have revealed closely related developmental states in Th17 cells, reflecting their plasticity. For example, given that Th17 cells share a differentiation pathway with Treg cells that, in turn, control Th17 cells, the Treg/Th17 axis is important for fine-tuning the intensity of inflammatory responses. An emerging picture shows that a combination of many factors involving IL-23, IL-2, CCR6, the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor (HIF) axis, metabolism (glycolysis and lipid synthesis), retinoic acid, glucocorticoids, melatonin, Wnt pathways, and salt act in synergy to regulate the Th17/Treg balance and inter-Th17 subset balance. Therapeutic interventions that can tune such balances would be efficacious when accompanied by our attentiveness to the spatial and temporal dynamics of Th17 cells. A comprehensive understanding of biochemical and cellular factors underlining these subtle regulations would give us a more integrated view that would hopefully help increase therapeutic options for many cases of autoimmune and inflammatory diseases and predisposed individuals.
