III. Department of Medicine, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
PLoS Pathog. 2022 Apr 21;18(4):e1010430. doi: 10.1371/journal.ppat.1010430. eCollection 2022 Apr.
Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.
金黄色葡萄球菌经常在脓毒症患者中被检测到，因此它是全球范围内的一个主要健康负担。CD4+T 辅助细胞通过支持抗体产生和吞噬作用参与对金黄色葡萄球菌的免疫反应。特别是分泌 IFN-γ和 IL-17A 的 Th1 和 Th17 细胞，参与了人类和小鼠系统性金黄色葡萄球菌感染的控制。为了研究 T 细胞在严重金黄色葡萄球菌感染中的作用，我们建立了一种小鼠脓毒症模型，在该模型中肾脏被确定为细菌负荷和 Th17 细胞丰度最高的器官。在该模型中，IL-17A 而非 IFN-γ 是控制细菌所必需的。使用 Il17aCre × R26YFP 小鼠，我们可以证明 Th17 命运细胞产生 Th17 和 Th1 细胞因子，表明 Th17 细胞具有高度的可塑性。肾脏 Th17 命运细胞的单细胞 RNA 测序揭示了它们的异质性，并在 Th17 细胞群体中鉴定出一个具有 Th1 表达谱的簇，而在 Th17 细胞中缺乏 T-bet/Tbx21 的小鼠中则不存在（Il17aCre x R26eYFP x Tbx21-flox）。在这些小鼠中，阻断 Th17 向 Th17 命运细胞的转化导致金黄色葡萄球菌组织负荷增加。总之，我们强调了 Th17 细胞在控制系统性金黄色葡萄球菌感染中的作用，并表明 T-bet 在 Th17 细胞中的表达对于清除细菌是必需的。虽然针对 Th17 细胞免疫反应是自身免疫的重要治疗选择，但沉默 Th17 细胞在细菌感染中可能会产生有害影响。
